Morphometric characteristics and relative numbers of neurons belonging to different neurochemical types in the nuclei of the Preglomerular complex and also in the Glomerular nucleus of the Oncorhynchus masou brain.
\r\n\tSolar radiation is the radiant energy that originated from the sun in the form of electromagnetic radiation at various wavelengths. Solar radiation is the source of renewable energy and can be captured and converted into various forms of energy (e.g. electricity and heat) using different technologies.
\r\n\tA very vast amount of solar energy reaches the atmosphere and surface of the earth and solar energy has been used for heating purposes for a very long-time and after solar cells’ invention in 1954, solar cells have also been used widely for electricity generation. Solar cells convert the sunlight into electricity by the creation of voltage and electric current through the so-called photovoltaic effect.
\r\n\tPhotovoltaic (PV) solar energy has attracted significant attention in the recent decade as a reliable source for power generation due to various merits such as the free source of energy, abundant materials resources, environmentally friendly and noise-free, longtime service life, requiring low maintenance, technological advancements, market potential, and very importantly, low cost. The growth of using photovoltaic (PV) solar energy as a promising renewable energy technology, is being increased more and more worldwide. Therefore, much further research is needed for possible future developments in the field of solar photovoltaic energy.
\r\n\tThe aim of this book is to provide detailed information about solar radiation as the source of photovoltaic (PV) solar energy for a broad range of readership including undergraduate and postgraduate students, young or experienced researchers and engineers.
\r\n\tThis should be accomplished by addressing the various technical and practical aspects of solar radiation fundamentals, modeling and the measurement for photovoltaic (PV) solar energy applications.
\r\n\tThe majority of this book should describe the basic, modern, and contemporary knowledge and technology of extraterrestrial and terrestrial solar irradiance for photovoltaic (PV) solar energy.
\r\n\tThe book covers the most recent developments, innovation and applications concerning the following topics:
\r\n\t• Fundamental of solar radiation and photovoltaic solar energy
\r\n\t• Solar radiation and photovoltaic solar energy potential
\r\n\t• Solar irradiance measurement: techniques, instrumentation and uncertainty analysis
\r\n\t• Solar radiation modeling for photovoltaic solar energy applications
\r\n\t• Solar monitoring and data quality assessment
\r\n\t• Solar resource assessment and photovoltaic system performance
\r\n\t• Solar energy and photovoltaic power forecasting
\r\n\tThese are accompanied with other useful research topics and material.
",isbn:"978-1-83968-859-1",printIsbn:"978-1-83968-858-4",pdfIsbn:"978-1-83968-860-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"4c3d1319d7286e81bfb15c1f4b20460a",bookSignature:"Dr. Mohammadreza Aghaei",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9862.jpg",keywords:"Solar Radiation Modeling, Solar Data Assessment, Solar Monitoring, Solar Radiation Forecasting, Solar Irradiance Measurements, Solar Instruments, Solar Spectral Distributions, Uncertainty Analysis, Solar Cell Technologies, Photovoltaics (PV), Solar Resource Assessment, Photovoltaics Power Forecasting",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 17th 2020",dateEndSecondStepPublish:"October 15th 2020",dateEndThirdStepPublish:"December 14th 2020",dateEndFourthStepPublish:"March 4th 2021",dateEndFifthStepPublish:"May 3rd 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A senior researcher in the field of photovoltaic solar energy, a postdoctoral scientist at Eindhoven University of Technology (TU/e), Chair of the WG2: reliability and durability of PV in EU COST PEARL PV.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"317230",title:"Dr.",name:"Mohammadreza",middleName:null,surname:"Aghaei",slug:"mohammadreza-aghaei",fullName:"Mohammadreza Aghaei",profilePictureURL:"https://mts.intechopen.com/storage/users/317230/images/system/317230.jpg",biography:"Mohammadreza Aghaei is a senior researcher in the field of photovoltaic solar energy, Eindhoven University of Technology (TU/e), The Netherlands. He is chair of the Working Group 2: reliability and durability of PV in European Cooperation in Science and Technology, COST Action PEARL PV.\nHe received the M.S. degree in electrical engineering from the Universiti Tenaga Nasional (UNITEN), Selangor, Malaysia, in 2013, and the Ph.D. degree in electrical engineering from the Politecnico di Milano, Milan, Italy, in 2016.\nHe was a Postdoctoral Scientist with Fraunhofer ISE and Helmholtz-Zentrum Berlin (HZB)-PVcomB, Germany, in 2017 and 2018, respectively. He is a Guest Scientist with the Department of Microsystems Engineering (IMTEK), Solar Energy Engineering, University of Freiburg since 2017. He is currently a Postdoctoral Scientist with the Design of Sustainable Energy Systems Group, Eindhoven University of Technology (TU/e), The Netherlands. He has authored numerous publications in international refereed journals, book chapters, and conference proceedings. The main his research interests include Solar Energy, Photovoltaic systems, PV monitoring, LSC PV, solar cells, machine learning, and UAVs.\nDr. Aghaei is a member of the International Energy Agency, PVPS program-Task 13 and International Solar Energy Society, and also an MC member in EU COST Action PEARL PV.",institutionString:"Eindhoven University of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Eindhoven University of Technology",institutionURL:null,country:{name:"Netherlands"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"10",title:"Earth and Planetary Sciences",slug:"earth-and-planetary-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"5962",title:"Estuary",subtitle:null,isOpenForSubmission:!1,hash:"43058846a64b270e9167d478e966161a",slug:"estuary",bookSignature:"William Froneman",coverURL:"https://cdn.intechopen.com/books/images_new/5962.jpg",editedByType:"Edited by",editors:[{id:"109336",title:"Prof.",name:"William",surname:"Froneman",slug:"william-froneman",fullName:"William Froneman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"46438",title:"Participation of Neurochemical Signaling in Adult Neurogenesis and Differentiation",doi:"10.5772/58306",slug:"participation-of-neurochemical-signaling-in-adult-neurogenesis-and-differentiation",body:'The revealed peculiarities of structural and neurochemical organization and description of basic histogenetic processes (proliferation, migration and neuronal cell differentiation) during the brain forming in fish, which have signs of fetal organization, widen the existing knowledge about histogenesis of these structures in postembryonic development. It seems conceivable, that during postembryonic development in teleost fishes some neurotransmitters and gaseous mediators (NO and H2S) act as factors, which initiate and regulate the cellular and the tissues processes of genetic program during the brain development. We suppose the presence of epigenetic control of adult neurogenesis in salmon brain via highly coordinated nonsynaptic cell–cell signaling. This communication engages the neurotransmitters GABA and dopamine whose extracellular concentrations depend on neuroblasts number and high affinity uptake systems in neural stem cells. Neuroblasts release GABA providing a negative feedback control of stem cell proliferation and instructing them on the size of the neuroblast pool. We suggest that in salmon brain exist strong control mechanisms of neuroblast production. The data provided by our study add to our general understanding, that peculiarities of distribution of classical neuromediators (GABA, catecholamines) and gasotransmitters (NO and H2S) are directly connected with ability of the fishes brain to grow during the animal entire life. We suggest, that some classical neuromediators (GABA, catecholamines) and gasotransmitters (NO and H2S) not only regulate functional activity of neurons and modulate synaptic transmission in mature neural networks, but also are regarded as inductors of the fishes brain development (morphogenetic factors) in postembryonic ontogenesis. We propose that dopamine and GABA act as homeostatic signals to regulate neuroblast production. This confirmation is proved by finding of the phenotypically immature elements, expressing the above mentioned molecules in proliferating brain areas, in the three-year-old salmon brain, and of elements, which owe morphology of radial glia. The presence of enzymes, synthesizing gasotransmitters in the brain areas, which are expressing proliferative cell nuclear antigen PCNA, have proved their participation in regulation of postembryonic neurogenesis.
In the fishes, which preserve fetal state during long time (salmon and carp), such markers as NO and H2S in periventricular proliferative areas may present in different ratios. This is consistent with the hypothesis that in functionally similar complexes in animals the different signal transduction systems may be involved. In contrast to widespread neurogenetic model Danio rerio, the development of the salmon and sturgeon nervous system occurs during long time. As it follows from our data, the development of different CNS structures in the Oncorhynchus masou brain is characterized by evident heterochrony, so the cells of caudal brain regions gain features of phenotypical specialization earlier than in the forebrain structures. We suggest that the brain of these animals during a long time preserves the signs of fetal organization and low differentiated cells presence confirms this hypothesis.
Last years, certain attention of neuroscientists of different profile was turned to participation in the work of the brain «gaseous intermediaries»: nitric oxide (NO) and hydrogen sulphide (H2S). Their presence is found in the brains of representatives of different groups of vertebrates: from the Agnatha to human. The few data points to a high degree of variability in the distribution of NO-ergic neurons in the fish brain [1-3], and information about the involvement of nitric oxide and hydrogen sulphide in the functional activity of nervous system of fish is unordered and contradictory. This draws attention to the fact that the relative number of NO-synthesizing neurons and glial cells in the sensory, motor and integrative centers of the brain fish significantly exceeds that of terrestrial vertebrates, in particular, mammals [1, 4, 5]. This implies a wide and varied participation of NO in the metabolism of neurons and glial cells in the central nervous system of fish compared with mammals. However, information about the relationship of the NO-producing neurons of the brain of fish with the systems of classical neurotransmitters such as acetylcholine, catecholamines and GABA, are practically absent. Virtually nothing is known about the distribution of H2S-producing systems in the CNS of bony fishes. These investigations are of particular importance in connection with the emerging data on morphogenetic the role of classical and gas intermediary in the formation of the central nervous system of vertebrates [6].
The brain of fish has a unique vertebrates feature - it grows with the organism during all life. In connection with this fish is a model object for the study of embryonic and postembryonic development of the CNS, to influence these processes of various factors. It is shown that in the brain of adult vertebrate a system of cambial elements remains, the activity of which allows to replenish the population of neurons and glial cells in the course of a long period after birth [7]. Currently the mechanisms of pre-and postnatal morphogenesis of the brain in the fish, which for a long time secures the larval state, virtually have not been studied [8-10].
Especially it concerns the role of the so-called «radial glial cells» in the processes of morphogenesis of the brain, the availability and distribution of proliferative areas in the brain of adult fish. The results of the research on Danio rerio showed that the newly formed cells moving from periventricular areas deep inside the brain, where they differentiate into neurons [11]. It was found that the centers of proliferation are localized along the rostro-caudal axis of the brain [7]. The interest to the study of these processes in fish is caused by the fact that the «radial glia» may be connected with the processes of migration and differentiation of neurons and glial cells in the prenatal period, large quantities present in the brain of a fish and in the adult state (unlike other vertebrates). However, in spite of the available literature information, participation of the radial glia (RG) is in the process of neurogenesis adult animals and little studied. One of the reasons for the lack of such information is a small number of examined in the terms of species and groups of fish, the absence of reliable markers of the RG in lower vertebrates.
Sturgeon and salmon fish, which have become the main objects of our research, represent the most ancient group of vertebrates, which are the most primitive branches ray-finned fish [12-13]. The information about the development of the brain sturgeon and salmon, the relations of embryonic and a definitive parts in the structure of the pre-and postnatal neurogenesis, organization and formation of the neuromediating and modulating brain systems in the literature are extremely limited. This concerns especially the sturgeon fishes, the evolution of which was carried on the pedomorphosis way, which is characterized by the slowing of organs or of their systems and the preservation of the adult embryonic status of relevant features.
The purpose of this chapter is to explore the organization, projection features and relationships of signal-transduction systems, producing a classic neurotransmitters (catecholamines, acetylcholine, gamma-aminobutyric acid-GABA) and gazotransmitters (nitric oxide and hydrogen sulphide), in the brain of fish and evaluate their participation in the processes of the post-embryonic morphogenesis the CNS.
Molecular-biological approaches associated with identifying of histochemical and immunohistochemical activity of mediators or enzymes of their synthesis were used for characteristics of neurotransmitter systems structures of the brain and spinal cord fish. Specific antibodies are also used by us in identifying of proliferative cell nuclear antigen (PCNA), transcription factor Pax6 and calcium binding protein parvalbumin. To investigate the relationship of brain applied marking nerve fibers using carbocyanin dye DiI. To track ascending mediatorically specific projections of catecholaminergic cells was used the immunofluorescence method of marking tyrosine hydroxylase in combination with the marking of the DiI.The histochemical reaction on NADPH-diaphorase (NADPH-d, NF 1.6.99.1). Experimental procedures were conducted in accordance with European Community guidelines on animal care and experimentation. The animals were deeply anesthetized with 0.03% tricain methanesulfonate (MS-222, Sandoz) and perfused transcardially with 50 ml of 0,63% saline followed by 200 ml of a fixative containing 4% paraformaldehyde in 0.1 M phosphate buffer (PB), pH 7.4. The brains were then removed from the skull, postfixed in the same fixative for 5 hours, washed in PB at 4°C overnight and then placed in a 30% sucrose solution for cryoprotection.
Fifty-micron-thick transverse sections were cut on a cryostat and collected in cold PB and, after several washes in PB, processed for NADPH-diaphorase histochemistry. Free-floating sections were incubated in a medium made up of 1mM β-NADPH, 0.8 mM nitro blue tetrazolium, and 0.06% Triton X-100 in 0.1 M phosphate buffer (pH 7.6), at 37˚C for 2 hours [14]. All chemicals were purchased from Sigma. After incubation, the sections were rinsed in PB, mounted on gelatin-coated glass slides, and air-dried overnight. The following day they were dehydrated cleared in xylene, and coverslipped with Entellan (Merck, Darmstadt, Germany).
In order to determine the specificity of the histochemical reaction, the following controls were carried out: incubation without the substrate β-NADPH, and incubation without the chromogen nitro blue tetrazolium in order to rule out possible nonspecific formation of reaction product. In all cases, no residual reaction was observed.
For histochemical staining of cholinergic neurons in the brain of fish we used marking of choline acetyltransferase (ChAT; NF 2.3.1.6.). Method was performed on fishes whose brains were fixed at 4°С for 2 h in 1% solution of paraformaldehyde based on cacodylate buffer (0.1 M) with sucrose (0.32 М; рН 5.0). The material was washed out in cacodylate buffer (рН 5.2) with sucrose for 18 h with sevenfold change of this solution. Frontal and sagittal 50-μm-thick slices were prepared with a freezing microtome. To exclude nonspecific transferase activity, 20 mM diisopropyl fluorophosphate (DFP), 10 % sucrose, and 25 mM cacodylate buffer were added to the incubation medium (рН 6.0) cooled to 4°С ; this medium was placed on an ice bath (0-4°С) for 1 h. After preincubation, the slices were placed in the incubation medium (рН 6.0) with the following final concentrations (mM): cacodylate buffer, 25; DFP, 1.0; choline chloride, 4.0; lead nitrate, 1.0; acetyl-CoA, 0.3, and 5% sucrose. The sliced were thermostated at 37°С for 2 h, washed out in distilled water, and treated in 5% solution of ammonium sulfide. Then, the slices were post-fixed for 5 min in 5% solution of formaldehyde based on cacodylate buffer (0.1 М; рН 5.2) with sucrose (0.32 М), dehydrated, and embedded in balsam. To estimate the specificity of reactions to ChAT, we carried out a few control experiments. In the first control series, we excluded DFP from the incubation medium. In the second control series, cetyl-CoA or choline chloride were absent in the incubation medium. In the third control series, we added chloracetylcholine-perchlorate (10 mM) to the DFP-containing pre-incubation medium; the incubation period was increased to 1.5-2 h. In all control experiments, a positive reaction was absent.
Immunohistochemical methods. Fishes were kept in aquaria with aerated seawater at 15-17°С. Before experiments, fishes were anesthetized in the cuvette with 0.1% solution of tricaine methanesulfonate (MS-222; Sigma, USA) in seawater for 10-15 min. The brains of fishes were fixed for 2 h at 4°С in 4% solution of paraformaldehyde dissolved in phosphate buffer (0.1 M, рН 7.2). For morphological analysis, the obtained material was embedded in paraffin according to a standard technique and stained by Nissl. In the course of immunohistochemical studies, we identified the elements containing GABA, tyrosine hydroxylase (TH), parvalbumin (PA), neuronal nitric oxide synthase (nNOS), proliferative cells nuclear antigen (PCNA), transcription factor Pax6 and cystathionine β-synthase (CBS). For this purpose, we used indirect avidin-biotin-peroxidase (ABC technique) or streptavidin-biotin staining. The material was washed out for 24 h in 30% sucrose solution. Transverse 50-μm-thick slices of the fish brain were prepared using a freezing microtome. Free-floating slices were incubated at 4°С for 48 h in the presence of monoclonal mouse antibodies against GABA (ICN Biomedicals, USA; dilution 1:4000) and tyrosine hydroxylase, TH (Vector Laboratories, USA; dilution 1:5000), PCNA (Dako, Denmark; 1:4000), monoclonal antibodies against human transcription factor Pax6 (Chemicon, USA; 1:3000), monoclonal antibodies frog against PA (ICN, Biomedicals, USA; 1:4000), rabbit polyclonal antibodies against nNOS (ICN, Biomedicals, USA; 1:5000), monoclonal antibodies mouse against CBS (Abcam ab54883, England 1:5000). Then, the slices were incubated with secondary biotin-conjugated horse antibodies against mouse immunoglobulins (Vector Laboratories, USA) for 2 h at room temperature and washed out three times in 0.1 М phosphate buffer. To reveal localization of NO-ergic neurons and fibers, we used a technique of indirect streptavidinbiotin immunohistochemical labeling of NOS. The slices were incubated with primary polyclonal rabbit antibodies against nNOS (IСN Biomedicals, USA; dilution 1:5000) at 4°С for 24 h. After three washings out in phosphate buffer, the slices were incubated with secondary biotin-conjugated goat antibodies against rabbit immunoglobulins (Biomedicals, Germany) at room temperature for 2 h. The material was washed out three times in phosphate buffer. Then, the slices were incubated in the presence of the streptavidin-peroxidase complex (Biomedicals, Germany) at room temperature for 2 h and again washed out three times in phosphate buffer. Immunohistochemical reactions were visualized using a standard avidinbiotin system (ABC; Vectastain Elite АВС Kit; Vector Laboratories, USA). To identify the reaction products, the slices were incubated in a substrate for detection of peroxidase (VIP Substrate Kit; Vector Laboratories, USA); the process of staining was controlled under a microscope. Then, the slices were washed out in three changes of phosphate buffer, mounted on slides, dehydrated using a standard technique, and embedded in balsam. To estimate the specificity of the immunohistochemical reaction, we used a technique of negative control. The masu brain slices were incubated in a medium containing 1% nonimmune horse serum (instead of primary antibodies) for 48 h, and then all procedures were performed as was described above. In all control experiments, the immunopositivity in the studied cells was absent.
To study projections of the preglomerular complex and glomerular nucleus, we used the carbocyanine dye 1,1΄-dioctadecyl-3,3,3΄,3΄-tetramethylindocarbocyanine perchlorate, DiI (Aldrich, Sigma, USA). The brains of fishes were fixed for 24 h in 4% solution of paraformaldehyde; then, crystals of the above dye were introduced in the region of the anterior and medial preglomerular and mammillary bodies. The obtained preparations were incubated in 4% solution of paraformaldehyde with the addition of 0.01% ethylenediamine tetraacetic acid (EDTA) at room temperature. Frontal, sagittal, and horizontal slices (50 μm thick) were prepared using a vibratome (VIBRATOME 3000; Sectioning system, Germany) and embedded in glycerine. To visualize the marker, we used an optical system, AXIOPLAN-2, Imaging (Gerinang, Germany). Preparations with DiI-marked structures were photographed using a optical system AXIOPLAN-2, Imaging (Gerinang).
Immunofluorescent labeling of tyrosine hydroxylase (TH) combined with retrograde labeling of neurons with the carbocyanine stain DiI was used to study the brains of Amur bitterlings Rhodeus sericeus. Specimens were fixed in 4% paraformaldehyde for one day, after which crystals of stain were placed in the ventral part of the telencephalon. Specimens were incubated in 4% paraformaldehyde supplemented with 0.01% ethylenediaminetetraacetate (EDTA) at room temperature for one day. Frontal, sagittal, and horizontal vibratome sections of thickness 50 μm were cut and incubated with primary mouse monoclonal antibodies against TH (Vector Laboratories, Burlingame, USA) diluted 1:1000 at 4°C for two days. Sections were then incubated with secondary fluorescent antibodies conjugated with Alexa 546 (Invitrogen Molecular Probes, USA) diluted 1:300 overnight. TH localization was studied using a Leica DM 4500 fluorescent microscope (Germany). Labeled TH and the carbocyanine label were visualized using a Leica TSC SPE confocal laser system (Germany).
Immunoperoxidase labeling of fragmented DNA chains, (TUNEL-labeling). To reveal apoptotic cells, we used a technique for immunoperoxidase labeling of fragmented DNA chains. After 2-h-long fixation in 4% solution of paraformaldehyde based on 0.1 M phosphate buffer (рН 7.2), dissected parts of the brain were washed out for 24 h in 0.1. M phosphate buffer. Then, these samples were put in 30% solution of sucrose based on phosphate buffer (0.1 М) for cryoprotection and kept in this solution up to full immersion. Frontal and horizontal slices (20 μm thick) were prepared using a freezing microtome. To identify TUNEL-positive structures, we used a immuno-peroxidase identification system, ApopTag Peroxidase In Situ Apoptosis Detection Kit (Chemicon International Inc., USA). For blocking endogenous peroxidase, the slices were incubated in 1% solution of hydrogen peroxide for 3 min and then washed out two times for 5 min in phosphate buffer. The slices were covered with a smoothing buffer (75 μl) and kept for 10 sec at room temperature. Then, the slices were slightly dried, subjected to the action of TdT enzyme (55 μl/5 cm2), incubated in a humid chamber for 1 h at 37°С, and immersed in a stop buffer for 10 min. The slices were washed out in phosphate buffer at room temperature (three times for 1 min with changing of the solution), again dried, covered with antidioxygenin conjugate (65 μl/5 cm2), and incubated in a humid chamber for 30 min. To detect the reaction products, cerebral slices were incubated in the substrate for identification of peroxidase (VIP Substrate Kit; Vector Labs, USA) with control of the development of color under a microscope, washed out in three changes of phosphate buffer, and mounted on glass slides. The cell nuclei were subjected to final staining with methyl green according to the technique of Brasher [15]. The preparations obtained were dewatered using a conventional technique and embedded in balsam. Morphometric processing was performed using an inverted-stage microscope, Axiovert 200M, equipped with a module, ApoTome, and digital cameras, Axio Cam MRM and Axio Cam HRC (Carl Zeiss, Germany).
The measurements were performed at ×400 magnification in five randomly chosen fields of vision for each studied region. The proliferation index (PI) and apoptosis index (AI) were calculated per 1 mm2 of the section using the following formulas:
PI = (n of the PCNA-positive nuclei × 100%) ÷ total n of the nuclei and
AI = (n of TUNEL-positive fragments × 100%) ÷ total n of nuclei
Parametric comparison (Student’s t-test) was used for estimation of the intergroup differences. The data obtained were processed using Statistica and Excel software. Numerical data are presented below as Means ± s.e.m.
Studies suggest that in the salmon′s brain at different stages of postembryonic development two forms of intercellular communications exist. The first form occurs in the early stages of postembryonic development and represents cells cooperation, carried out paracrinic in the period when cells have not developed processes and synaptic structure yet. However, such little differentiated cells are already able to express the specific synthetic machinery for some neurotransmitters and their synthesizing enzymes, gaseous intermediates, transcription factors and other substances (Fig. 1A-D). We suppose that most of the synthesized signals in this period are involved in the regulation of neuronal targets, differentiation and expression of their specific phenotype, acting as a morphogenetic factors. This is consistent with the Ugryumov concept [6] regarding the development of the mammalian brain in the embryonic period of ontogenesis. Already in the early stages of post embryonic morphogenesis of masou salmon, simultaneously two systems of neurochemical signaling exist, the dopaminergic and GABA-ergic systems, providing paracrinic and perhaps autocrinic influence on target cells until the formation of synaptic contacts and the beginning of neurotransmission with specific interneuronal connections. Study on the eal Anguilla anguialla showed that the maximum concentration of dopamine D1 receptors is found in periventricular zones [16] which represent a matrix areas of the brain, where neurogenesis continues throughout the life of the animal. Consequently, the cells located in proliferating areas are targeted for the regulatory impact of dopamine. These cells are localized on the territory of the largest vascular plexus (forebrain and caudal medullar), and synthesize in these regions some substances, like a dopamine and GABA, which then may be excreted in the portal system blood flow and further into the general circulation system, providing regulatory endocrine effects on the peripheral organs [17]. Thus, there is considerable justification to suggest that in the hypophysotrophic areas of the diencephalon and medulla oblongata of the brain of juvenile salmons O. masou, dopamine and GABA in undifferentiated cells of periventricular and subventricular areas are inducers of development (morphogenetic factors).
A - immunolocalisation of tyrosine hydroxilase (TH) in parvocellular preoptic nucleus (Pop), B - proliferative nuclear antigen (PCNA) in dorsal thalamus (DTh), C - neuronal nitric oxide synthase (NOS) in pretectal (Ptn), dorsal (DTN), ventro-medial (VMTN) thalamic nuclei, D - transcriptional factor Pax6 in periventricular diencephalon of 6-month-old Oncorhynchus masou. Immunonegative border of dorsal neuromers on A, delineated by a triangle, the cluster of immunopositive cells on D, delineated by rectangle. Inf – infundibulum, FR – fasciculus retroflexus, Pt – pretectum. Scale: А, C – 100 μm, B, D – 50 μm.
Along with the specified form of intercellular signaling in salmon brain, in ontogenesis there is the development of specific system of forebrain activation and development of the system of remote intercellular signaling. The source of these directed connections are the nuclei of preglomerular complex [18]. Development of projective systems of salmon take place simultaneously with the formation of the structure of preglomerular complex [19]. In the brain of non mammalian vertebrates the volume of sensory projection zones increases during all their life and is provided due to the proliferation of neural stem cells located in the areas of special neurogenetic niches [10]. It is connected with the necessity of adaptation of the CNS of such animals to increase the size of the body and increased inflow of primary sensory information. We believe that a dopamine, GABA-and NO-ergic systems in the brain of salmon participate in regulation of some basis histogenetic processes, such as a cell migration and differentiation of neuro- and gliospecific lines, because the nuclei of preglomerular complexes contain morphologically and neurochemically heterogeneous cell populations (table. 1) represented by the different stages of ontogenesis of major cell types. Cells formed in the proliferative (PCNA-containing) diencephalic areas migrate to the region of preglomerular complex, where their subsequent differentiation and growth take place. These processes are regulated by dopamine and GABA, that indicates the presence of D1 and D2 dopamine receptors [16, 20] and GABAB benzodiazepine receptors [21] in these nucleus of fish. A critical step prevalence of paracrinic relations in the salmons brain can be considered the period before the formation of the blood brain barrier (BBB), which in salmon brain is formed during the first year of life (according to [22]). In the next period of ontogenesis, the formation of the specific connections and the development of cellular processes of neurons and synaptogenesis take place. Today much data exist about the participation of radial glia in the processes of postembryonal neurogenesis by asymmetric mitoses in which one daughter cell remains in the periventricular area and has a rounded shape, while the other has a long process, which may later be eliminated through somal translocation [23]. It was shown that during embryogenesis of human, the predecessors of dopaminergic neurons in the basal part of the midbrain have the morphology of radial glia [24]. Immunolabeling of radial glia cells in salmon′s brain in different ages (Fig. 2 (A-D), as well as evidence that the TH-and GABA-ip cells were located on the territory of PCNA-ip proliferative zones and together with PCNA marked the neuromeric structure of diencephalon and medullar part of the brain, certainly shows that dopamine and GABA-ergic signaling participates in the processes of postembryonic neurogenesis of the salmon′s brain, as inductors of development. Our data are consistent with the labeling of some rhombomeres in the brain in an embryo of sharks Scyliorhinus canicula [25].
\n\t\t\t\tNuclei\n\t\t\t | \n\t\t\t\n\t\t\t\tNeuronal nitric oxide synthase (nNOS)\n\t\t\t | \n\t\t\tCholine acetyltransferase(ChAT) | \n\t\t\t\n\t\t\t\tGABA\n\t\t\t | \n\t\t\tTyrosine hydroxylase(ТН) | \n\t\t\tParvalbumine(PA) | \n\t\t|||||
Size of cells (μm) | \n\t\t\tTotal number (%) | \n\t\t\tSize of cells (μm) | \n\t\t\tTotal number (%) | \n\t\t\tSize of cells (μm) | \n\t\t\tTotal number (%) | \n\t\t\tSize of cells (μm) | \n\t\t\tTotal number (%) | \n\t\t\tSize of cells (μm) | \n\t\t\tTotal number (%) | \n\t\t|
Glomerular | \n\t\t\t8-7 II 10-8 II 12-10 III | \n\t\t\t30±4 | \n\t\t\t20-12 I 18-12 I 14-6 IV | \n\t\t\t18±2 | \n\t\t\t9-6 II 7-7 II 12-6 IV 14-7 IV | \n\t\t\t50±6 | \n\t\t\t9-7 II 10-6 II 15-6 III 17-8 IV | \n\t\t\t12±2 | \n\t\t\t6-6 II 11-7 II 12-9 III 13-6 IV | \n\t\t\t48±4 | \n\t\t
Anterior Preglomer. | \n\t\t\t10-8 I 12-7 III 14-8 III 15-6 IV | \n\t\t\t24±3 | \n\t\t\t12-9 III 13-8 III | \n\t\t\t9±1 | \n\t\t\t20-13 I 12-12 III | \n\t\t\t47±5 | \n\t\t\t8-6 II 10-7 II 12-9 III 14-6 III 12-6 IV | \n\t\t\t14±2 | \n\t\t\t10-8 II 11-7 II 13-10 III | \n\t\t\t45±5 | \n\t\t
Medial Preglomer. | \n\t\t\t10-8 II 12-9 III 13-8 III | \n\t\t\t21±3 | \n\t\t\t12-9 III 13-10 III 14-11 III | \n\t\t\t12±1 | \n\t\t\t8-7 II 10-7 II 12-9 III | \n\t\t\t32±4 | \n\t\t\t9-9 II 10-7 II 12-9 III 14-7 IV | \n\t\t\t8±1 | \n\t\t\t9-7 II 10-8 II 13-10 III | \n\t\t\t30±3 | \n\t\t
Morphometric characteristics and relative numbers of neurons belonging to different neurochemical types in the nuclei of the Preglomerular complex and also in the Glomerular nucleus of the Oncorhynchus masou brain.
Footnotes. Roman numerals (in brackets) indicate the cell type. Mean values of the large and small diameters of neurons (М ± m, μm) are separated by slashes.
Differentiation of cells in various parts of the salmon′s brain presents a heterochronical process. In caudal part of brain some reticulospinal cells, cells of nucleus raphi, nuclei of V, VII, IX and X pairs of cranial nerves, much earlier acquire the features of phenotypic specialization than in the structures of forebrain. Measurements of fractal dimension and some morphometric parameters (total length of branches, number of terminal branches, number of branching points, and cell area) were used for the quantification of morphological patterns of two spinal neuron groups in young Oncorhynchus masou at two ontogenetic stages [26]. During the 1st and 2nd years of life, the neurons of brainstem and spinal cord have enough developed dendrites and axons, which, however, have growth cones, indicating the continued postembryonic period of growth and development of these structures and their further differentiation. During the second year of life, the values of morphometric parameters and fractal dimension of neurons increased in both groups. Basic morphometric values correlated with fractal dimensions and conformed to morphological changes in the dendritic tree of the investigated neurons in ontogenesis. During the third year of life, in the nuclei of the brain and spinal cord large-differentiated cells expressing TH, GABA and parvalbumine in the motoneurons of ventral spinal column, nuclei of craniocerebral nerves, reticulospinal cells and some diencephalic nuclei were revealed [27].
Immunohistochemistry of tyrosine hydroxylase in a spinal cord (A) and tectum (B) of a one-year old O. masou, in the periventricular diencephalic (C, D) and the medullar (D) departments of a 3-year-old fish. The arrows show the radial fiber; and: rectangle delineated areas of radial fibers, forming the «end feet»; D: on the border between dorsal neuromeres the immunolabeling of TH is absent; E: rectangle delineated by interfascicular area containing the radial fiber. Scale: A, B, D-50 µm; D-100 μm.
Along with systems synthesis of classical neurotransmitters, immunolocalisation of transcription factor Pax6 was investigated, the marking of which adequately reflects neuromeric structure of the salmon′s brain in different ages (Fig 3 A, B). The early juveniles (3 and 6 months old) are the Pax6-ip cells do not have any processes and formed a small clusters corresponding to forebrain prosomeres (P1-P3), and in the medulla, such accumulations marked the rostral (R1-R2) rhombomeres (Fig. 3B). On the boundary of neuromeres labeling of PCNA and Pax6 were absent (Fig.3 A, D). In three-year old salmons the marking Pax6 was found in the cells and radial fibers, located in the periventricular and subventricular areas of diencephalon that corresponds to the data of labeling of Pax6 radial glia in the areas of postnatal neurogenesis of mammals [10]. On borders of the forebrain neuromeres the immunolabeling Pax6 in 3-years old individuals was absent. Expression of Pax6 was also found in glomerular nucleus and nuclei preglomerular complex that suggests about morphogenetic processes on the territory of the largest sensory center during postembryonal period. Immunolocalisation of Pax6 in specific cell clusters of glomerular nucleus, appropriated to some neuroanatomical zones, in which the differentiation of neurons, conducting various types of sensory signalization was revealed (Fig 3C. D). Studies suggest that factor Pax6 participates in the regionalization of the structure of the brain in postembryonal period, and its expression in different ages of salmon brain shows that the processes of neurodetermination and migration of cells, formed in proliferative areas of the brain in these age periods are regulated by means of this transcriptional factor. In the literature there are discrepancies regarding the organization and topography of dopamine, GABA-and NO-ergic complexes in the brain of different teleost fishes. Significant differences in the organization of the mediator systems in different fish species become more explainable, given the above mentioned scheme. We believe that neurotransmitter systems in the brain fish should be considered not only from the standard point of view of their definitive neuroanatomical structure, but must also take into account data on heterogeneous molecular phenotype of dopaminergic, GABA and, apparently, NO-ergic systems. Thus, for the establishment of homology, along with the systematic position, it is advisable to take into account the age, stage of development, physiological status and sex of the animal. In adult masou salmon and chum salmon the cells of Dc area of the telencephalon reach a high level of specialization and corresponding to the Ramon-Molener classification can be attributed to allodendric type.
Expression of transcription factor Pax6 in the brain of 3-month-old salmon O. masou (A and B) and 3-year-old trout (C and D) (immunoperoxidase staining, light microscopy). Accumulations of immunopositive cells in the diencephalon (A) and medulla (B). Part of the brain (in rectangles) labels its neuromeric structure, the sites without immunolabeling constitute the borders of forebrain P2 and P3 prosomers (black edges of arrows), arrows with a cut show accumulations of migrating cells. Radial glia in the optical tectum (C) and around dorsal neuromer (P2) in the diencephalon (D). Scale: A-100 μm, B-200 μm, C and D – 50 μm.
Such cells have been found only in the most mature individuals (of 4-5 years old) going to spawn. One of the forms of specialization of these cells is that they have a network of basal spiny dendrites. This corresponds to the estimated specialization of such cells as associative spiny interneurons participated in communications with other parts of the dorsal area in telencephalon. Widespread TH and GABA in the telencephalon of adult chum salmon indicates that species to this period of development, along with paracrinic (volume) neurotransmission, there is a distant form of neurotransmission, which is becoming the predominant further ontogenetic development and ageing of the animal. We suggest that the acquisition of spiny apparatus by the neurons in the dorsal (Vd) and internal (Vi) areas ventral zone can be considered as one of the stages of ontogenetic development of neurons in the brain, indicating the age-related changes in the organization of the salmon′s dopaminergic system. Formation of the system of neurochemical communication in the CNS of masou salmon in postembryonal period consists of two main stages. At the first stage the undifferentiated cells are located in matrix areas of the brain and expressed of specific syntheses (catecholamenes, GABA, NO, some transcription factors). These substances are acting in paracrinic interaction and involved in regulating basis histogenetic processes: cell proliferation, cell migration, differentiation of target cells and expression of a specific phenotype. Under the influence of these factors on the second step is the formation of specific relations, development of processes of neurons and sinaptogenesis.
As a model to test an alternative hypothesis, we studied the CNS of amur bitterling Rhodeus sericeus (Cyprinidae), coming to sexual maturity in the first year of life. The literature of the late twentieth century actively discussed some issues relating to the organization and topography catecholaminergic system of vertebrate’s brain detectable by methods formaldehyde-induced fluorescence (FIF) and IHC labeling of tyrosine hydroxylase. In this period, a hypothesis was formulated about the existence of dopamine deposited system in the brain of fish [28]. Data about neuromeric organization and molecular markers that define dopaminergic phenotype of neurons in Danio rerio, had recently published [29]. In the bitterling brain 3 main types of cells were verified. The first type consists of small round cells in the periventricular nucleus of the diencephalon and second one are formed by large pear-shaped or fusiform cells [30]. The cerebrospinalliquor-contacting cells (CSL) are the most common third type of catecholaminergic cells. According to the Meek classification [28], large cells and CSL-contacting cells at Amur bitterling can be attributed to the elements of dopamine deposited system. In the hypothalamus of bitterling were discovered a few CSL-contacting cells with a low level of activity TH, but cells were marked by gliocsalic acid. Some fish have similar features morphology of CSL-contacting cells (in particular, the presence of apical dendrite, turned into the lumen of the cerebral ventricle), and these cells are a FIF-positive, but do not contain enzymes synthesis of catecholamines (TH-negative). It was the reason for the assumption that such cells are not synthesizes catecholamines by themselves, but receives CE from external sources, in particular, liquor or from large dopaminergic neurons [31]. Data labeling catecholaminergic systems on other groups of vertebrates show that dopamine and norepinephrine dissolved in the cerebrospinal fluid are of greater importance for non mammalian vertebrates; but in mammals, the CSL-contacting cells at all have not been identified [32]. These confirm the observations obtained by us on the masou salmon.
Lack of Cyprinidae fish glomerular nucleus largely hinders establishing of homology between ascending sensory projections in the telencephalon with those of other fishes [33]. To identify sources of CA-ergic innervation of the ventral part of the telencephalon of bitterling investigated the projection of this area of the brain. Tracing part of dopaminergic fibers in the ventral telencephalon bitterling showed that along with intratelencephalic cell groups exists the extratelencephalic sources of innervation of the dorsal and ventral nuclei [30]. Sources of dopaminergic projections in the ventral part of the telencephalon are two populations of cells in posterior tuberculum of bitterling, namely large cells and small rounded cells. Such cells are projected on the dorsal and ventral areas of ventral telencephalic part respectively and are considered by us as the morpho-functional equivalents of meso-striatal and meso-limbic systems of mammals. Identification dopaminergic fibers in the dorsal region of telencephalon of D. rerio [31] suggests that teleostea have also equivalents of meso-pallial system.
Tyrosine hydroxylase in the neurons of the medulla oblongata Amur bitterling Rhodeus sericeus. A and B-neurons of interfascicular group, C, D-neurons of area postrema. Scale: A-C-100 μm; D-50 μm.
The peculiarities of localization of medullary neurons, morphology of the dendrites, and trajectories of the axon projections in the medulla of the Amur bitterling allow us to differentiate three groups of ТН-positive neurons, namely interfascicular cells, units related to the lobus vagus, and cells localized within the area postrema (Fig. 4 A-D). The 3-year-old masou salmon in all the above mentioned areas of the brain stem were also identified large TH-ip cells with clear features of phenotypic differentiation. However, along with differentiated ТН-positive elements of masou salmon we revealed previously not described alternative TH-positive elements, namely small undifferentiated cells, located on the territory of proliferative periventricular and subventricular zones [27]; numerous radial fibers, having different localizations in medullar part of CNS (Fig. 2E). We believe that the presence of such elements with clear features of fetal organization, as well as radial fibers in the brain 3-year-old masou salmon connected with the processes of postembryonic (adult) morphogenesis of the brain. The differentiated TH-ip neurons in salmon brain are functionally active to this period of ontogenesis elements of CA-ergic system. Study of the CA-ergic system in the medullary part of bitterling found pronounced features of specialization associated with the organization of medullary CA-ergic complexes. Analysis of these characteristics showed that of bitterling CA-ergic cells in neuronal networks of the medulla can fulfill the functions of local interneurons, projection long axon neurons, neurosecretory units, or sensory units. The morphology of interfascicular ТН-positive cells in the Amur bitterling brain allows one to regard their functional specialization as local interneurons, since they form intensely branched dendritic networks (Fig. 4A, B). All three groups of medullary TH-ip neurons of bitterling project their terminals to the longitudinal catecholaminergic tract. Therefore, it is appropriate to hypothesize that all these cells are relatively long-axon neurons projecting to the rostral part of reticular formation, isthmus, and secondary gustatory nucleus which are relay centres, between the primary sensory nuclei of medulla oblongata and sensory centers of the ventral thalamus. The ТН-positive cells of the vagus region and area postrema (supposedly dopaminergic) have access to the fourth ventricle; likely, these neurons are chemosensory units responsible for the relations between the cerebrospinal fluid and neuronal medullary systems (Fig. 4С, D). On the other hand, these two neuronal groups in the Amur bitterling differ from others in an extremely high level of TH activity; it cannot be ruled out that they can serve as a source of dopamine coming to the cerebrospinal fluid. The morphology of these neurons allows one to hypothesize that each of the three groups of medullary CA-ergic neurons in the Amur bitterling is involved in realization of at least two functions of the above-listed ones, while the cells associated with the lobus vagus can combine all three functions. In the masou salmon brain phenotypically mature types of TH-ip cells localized in similar areas of the medulla oblongata, can have a similar functional specialization (Fig. 2E). However, part of the identified by us TH-ip elements is located in the proliferative (PCNA-marked) areas of medulla oblongata [27] at the earlier stages of ontogenesis mark neuromeric structure of medulla oblongata. At later stages localization TH found in the fibres of radial glia in interfascicular region, on the territory of fossa romboidea, as well as in populations of small cells in periventricular and subventricular areas (Fig. 2E).
In the Amur bitterling the density of the distribution of such phenotypically not mature cell forms in the periventricular area of the brain is significantly lower than the masou salmon. We believe that the features allocation in medullar part of masou salmon and Amur bitterling confirm the assumption about the participation of dopamine as a morphogenic factor regulating brain development of fish in postembryonal period.
Study of the modulating influence gaseous intermediators to the classical system of neurotransmitters in the brain of fish previously had not been carried out. In our studies showed that the total nitroxidergic products in the nuclei of the brain stem in different fish species significantly exceeded the measure set for other groups of vertebrates and, particularly mammals. So, it is normal for different fish species NO-producing neurons were verified somato- and viscerosensor and visceromotor nuclei of medulla oblongata (V, VII, IX, X nuclei of craniocerebral nerves, Fig. 5), efferent octavo-lateral neurons, the nuclei of the isthmus, secondary gustatory nuclei, the nuclei of oculomotor complex (III, IV and VI nuclei of cranial nerves). Most of these nuclei in fish brain are cholinergic centers of brain stem involved in the innervation of brachiomotor muscles and some sensory inputs from the somatosensory, gustatory extra- and intraoral system, mechanosensory, octavolateral receptors. In fish due to low level of cephalization brain the most of the sensory inputs from the somatosensory (nucleus V), octavolateral, gustatory extraoral (nucleus VII), intraoral (nucleus IX) are concentrated on the territory of medullary part; therefore this sector is perceived by a large volume of incoming sensory information (see the diagram on Fig. 5). Despite significant interspecific morpho-adaptative differences, in Perciformes and Cyprinoid fish were identified similarities in the organization of medullar and spinal NO-producing centres. Participating NO in modulation of sensor systems in forebrain of mammals it was proved today [34]. We assume that in the medulla fish NO performs modulation of primary sensory centers, located in the nuclei of craniocerebral nerves. In the masou salmon brain all of the above mentioned nuclei, located in the stem and isthmus region are cholinergic and express nNOS (see the diagram on Fig. 5). Primary sensory nuclei (V, VII, VIII, IX and X), and secondary relay nuclei (secondary gustatory nucleus, the nucleus of the isthmus) in tha masou salmon brain, processing heteromodal sensory the information in the nuclei of preglomerular complex modulated by NO (Fig. 5). We assume that in the masou salmon brain NO is modulator of sensory and motor cholinergic centers.
Schematic diagram of sensory signals ascending from the nuclei V, VII, IX, X and octavo-lateral nerves of medulla oblongata to the telencephalon. In the left part are demonstrated the efferent ascending and descending projection, anterior, medial preglomerular nuclei and mammilar body O. masou labeling by the DiI [19]. NO-ergic nuclei of brainstem are shown by black, cholinergic-red circles. The other explanation see text.
Densitometric analysis of the CBS activity in different brain areas of masu salmon Oncorhynchus masou and carp Cyprinus carpio. Abscissa axis, brain areas; Ordinate axis, optical density (OD). Data are shown as M ± m. (a) CBS activity in neurons of dorsal telencephalon; (b) CBS activity in neurons of ventral telencephalon; (c) CBS activity in the optic tectum; (d) CBS activity in the cerebellum; (e) CBS activity in the spinal cord and medulla oblongata. Designations: Vv, Vd, Vl, ventral, dorsal, and lateral cell nuclei of the ventral telencephalon; Dd, Dc, Dl, dorsal, central, and lateral cell nuclei of dorsal telencephalon. blue columns-masu salmon; pink columns-carp.
The most important sensory center, conducting nociceptive information in fish’s brain is a nucleus raphi. We found that in different species of teleost fish the most of the neurons of the nucleus raphi superior and nucleus raphi inferior are expressed NADPH-d. This confirms the data installed on mammalian and human brain, that NO is a mediator of nociception [35]. The presence of nNOS-producing neurons and high level of activity NADPH-d in the nuclei of raphi, dorsal spinal cord fibers and sensory part of the nucleus of trigeminal nerve indicates participation of nitric oxide in the modulation signals of nociceptive and somatosensor centers of the medulla oblongata in fishes brain. Study of the localization of nNOS in some periventricular hypophysotropic nuclei in diencephalon of adult specimens of Amur bitterling showed that TH-ip and NO-producing system in periventricular and subventricular nuclei in general have similar localization and area of colocalisation these transmitters is periventricular nucleus of posterior tuberculum, where nNOS and TH were localized in small cells, forming ascending projections on the ventral telencephalon. In these cells NO can modulate synaptic plasticity of dopaminergic neurons and regulate the excretion of dopamine.
Study of physiological activity of hydrogen sulfide in the nervous system of mammals began recently [36], and identifying its role in the central nervous system of fish previously had not been carried out. The results of researches conducted on fish suggest that hydrogen sulfide acts as an intermediary, regulating a number of enzymatic reactions cells. Distribution of the enzyme synthesis of H2S in the CNS of fish is expressed species-specific features, perhaps reflecting their adaptation character and functional status of the animal. Cystathionine β-synthase in the brain of masu salmon Oncorhynchus masou and carp Cyprinus carpio was found in neurons of the ventral spinal column and medulla oblongata, fibers and cells of the cerebellum, optic tectum, and telencephalon. In all brain areas, the intensity of CBS labeling in neurons varied between moderate and high. We found interspecies differences in the immunolocalizatoin and optical density of CBS in different brain structures of masu salmon and carp. In carp, the medulla oblongata and spinal cord contained intensely marked vessels that were absent in masu salmon. In the brain of carp, H2S presumably functions as a predominant vasoregulator. H2S-producing systems in the brain of bony fishes have specific characteristics of organization and strong species-related differences that correlate with the specificities of neuromediators, for example, NO-producing, systems.
Comparative studies of localization CBS and densitometric data in various structures of the masu salmon and carp showed interspecific differences, having obviously adaptive value (Fig. 10). In different areas of the masu salmon brain revealed varicose or smooth microcytosculpture of afferents and their endings, which may indicate to synaptic or paracrinic (volume) methods of H2S release in different areas of the fishes brain.Currently shows the involvement of GABA in the regulation of the endocrine activity of hormones preoptico-pituitary complex at the early juveniles Salmo trutta fario [37]. On larval and early juvenile of this salmon species showed the participation of GABA-ergic innervation in the regulation of synthesis of peptide hormones of the pituitary, namely metencephalin and galanin [37]. In our research on different age groups of masu salmon, it was found that GABA-ip neurons are present in various parts of the brain: in the medulla oblongata, periventricular nuclei of diencephalon, mesencephalic tegmentum, the brain stem, the cerebellum and spinal cord (Fig. 11). In addition to the neural localization of GABA, it was identified small undifferentiated cells and radial fibers, localized in areas where the proliferative activity of cells persists in adults animals (Fig. 11A, D). These zones have been identified in the diencephalon on the territory of preoptical area, posterior tuberal, thalamic and hypothalamic areas; in the region of the central gray matter of mesencephalic tegmentum; in the interfascicular area of brain stem and in the periventricular zones in nuclei IX-X pairs of cranial nerves and the spinal cord. Patterns of distribution GABA-ergic elements in the masu salmon brain is similar with the distribution of TH-ip structures. This similarity manifests itself in the presence of both phenotypically mature cell forms and undifferentiated elements with periventricular and subventricular localization and marking of neuromeric structure of the brain. This immunomorphology of GABA-ergic structures, discovered in the different age groups of masu salmon, may indicate that, like dopamine, GABA should be also considered as morphogenetic factor affecting of postembryonic brain development.GABA-ergic neurotransmission characterized by a high variability of synaptic responses. In mammals, hydrogen sulfide regulates the condition of GABA-receptor of different subtypes, localized pre-and postsinapticaly [38]. In adult masu salmon in different areas of the brain and spinal cord, containing large projection cells, namely the dorsal tegmental nuclei, medial reticular formation, reticulospinal cells, neurons in the ventral spinal column were installed joint localization of GABA, PA and CBS (Fig. 7). These large-cells structures in the fish brain participate in the organization of fast motor responses [39]. In medullary regions of the medial RF and VSC of the masu salmon, the level of colocalization of CBS, GABA, and PA is rather high. It is believed that the presence of PA promotes the formation of buffer calcium systems that provide generation of repeated action potentials in neurons with high-frequency discharges (Fig. 7). The high level of colocalization of PA, cytochrome oxidase, and 2-deoxyglucose also indicates that the PA content is typical of neuronal systems characterized by a high level of oxidative metabolism [40]. It was demonstrated that the concentration of intracellular calcium in neurons and glial cells upon the action of H2S reversibly increases (due to the release of calcium from intracellular stores and its entry into the cell through the plasma membrane) [41, 42]. Such adenylate cyclase-dependent mechanisms of activation can also be realized in the magnocellular CBS-and PA-ip populations of myelencephalic cells of the masu salmon brain identified in our experiments. As was found, inhibition of H2S synthesis results in a significant decrease in the level of intracellular calcium. This confirms the conclusion on the appreciable effect of H2S-dependent pathways on the time characteristics of processes related to calcium homeostasis in the neurons [41].
Schematic diagrams of distribution of cystathionine-β-synthase (CBS)-, GABA-, and parvalbumin (PA)-immunopositive loci in frontal CNS slices of the masu salmon, Oncorhynchus masou (A-M). Zones of immunopositivity with respect to CBS, GABA, and PA are indicated by blue circles, red diamonds, and black asterisks, respectively. AC) Ansular commissure, AP) area postrema, Vv, Vd, Vl, and Vs) ventral, dorsal, lateral, and supracommissure zones of the ventral region, respectively, SGT) secondary gustatory tract, VMTN) ventromedial thalamic nucleus, VSC) ventral spinal column, Ha) habenula, GE) granular eminence, Gl) granular layer, Dd, Dl, Dm, and Dc) dorsal, lateral, medial, and central zones of the dorsal region, respectively, DLNT) dorsolateral nucleus of the tegmentum, DTN) dorsal thalamic nucleus, PVe) posterior ventricle, PC) posterior commissure, PTN) posterior tuberal nucleus, rV) root of the trigeminal (V cranial) nerve, MPoN) magnocellular preoptic nucleus; LH) lateral hypothalamus, LVe) lateral ventricle, LOT) lateral optic tract, CC) corpus cerebelli, MeRF) mesencephalic reticular formation, CeV) cerebellar valve, CeCh) cerebellar chiasm, PPoN) parvicellular preoptic nucleus, MLF) medial longitudinal fascicle, MRF) medial reticular formation, CeMl) cerebellar molecular layer, DTT) descending tract of the trigeminal nerve, OLen) octavolateral efferent neurons, MRB) Meynert’s retroflex bundle, OT) optic tectum, OCh) optic chiasm, ON) olivary nucleus, SlT) semilunar torus, PVO) paraventricular organ, PGN) preglomerular nucleus, AC) anterior commissure, LT) longitudinal torus, ATN), anterior thalamic nucleus, ATbN) anterior tuberal nucleus, PN) pretectal nucleus, RF) reticular formation, ST) solitary tract, CHtN) central hypothalamic nuclei, CC) central canal, CGl) central gray layer, NIII) oculomotor nucleus, NIV) nucleus of the trochlear nerve, NIX-X), nuclei of the glossopharyngeal and vagus nerves, respectively, NV) nucleus of the trigeminal nerve, NVII) nucleus of the facial nerve, IIIn) oculomotor nerve, IV) fourth ventricle, and VIIn) facial nerve.
Significant heterogeneity of CBS-ip, GABA-ip,and PA-containing subpopulations of neurons in all regions of the masu brain is indicative of the fact that such units belong to different neurochemical and electrophysiological systems. The density of CBS-, PA-, and GABA-ip cells in the masu salmon is maximum and constant in the magnocellular caudal cerebral regions, namely in the regions of localization of the reticulo-spinal neurons, “high-frequency” Mauthner cells, and ventral spinal cord (VSC) neurons. Cells of these types in fishes are involved in the organization and control of rapid motor reactions [43]. Н2S-dependent regulation of calcium release with participation of PA can influence the parameters of impulse activity due to shortening of the refractory period in the corresponding neurons after generation of action potentials and, therefore, can provide the animal with certain behavioral evolutionary preference. Thus, in the population of large inhibitory neurons containing enhanced concentration of intracellular Ca2+, the excretion of GABA in our opinion can be arranged with the help of hydrogen sulphide.
Study of the relationship between NO and H2S-producing systems in the masu salmon brain revealed that they were separate, non-overlapping system of intra-and intercellular signaling. The study of the distribution of NADPH-d positive, nNOS-and CBS-ip elements in different areas of the masu salmon brain, and some features immunolabeling of cells and fibers indicate that NO and H2S-producing systems are independent neural complexes that perform specialized functions in the work of local neural networks.
In the dorsal region of the telencephalon in masu salmon NO is predominant gasotransmitter, the effects of which release by paracrinical way. In the ventral region of the telencephalon prevails system of hydrogen sulfide synthesis. In the ventral region of the telencephalon high activity CBS was revealed. Perhaps this system has synaptic localization, significant morphological heterogeneity of cells in the dorsal nucleus (Vd) and varicose cytosculpture of the afferents. Apparently, in the telencephalon of masu salmon way to release the gasotransmitters affect the nature of their neuromodulatory effects.
In the periventricular area of diencephalon and optic tectum masu salmon were populated by both CBS and nNOS and NADPH-d-producing cells. The presence of NO and H2S-producing elements in these areas indicates possible participation of hydrogen sulfide and nitric oxide in morphogenesis these compartments of a brain. In masu salmon brain has been identified CBS-ip fibers of varicose type that penetrate the layer of Purkinje cells. The presence of such fibers and CBS-ip endings in interganglionic plexus of corpus cerebelli, possibly reflecting the sinaptical method of release of H2S in this area of the masu salmon brain. The presence of NO-ergic cells and fibers was shown in the cerebellum on different species of fish by histochemical marking of NADPH-d [4, 44, 45]. Detection of nNOS in eurydendroid cells of masu salmon cerebellum confirms received our earlier data on histological labelling of NADPH-d in the neurons of this type of fish [46]. According to Ikenaga with co-authors [47], most of the eurydendroid cells in fish are aspartat-ergic and receive GABA-ergic impulses from the Purkinje cells. According to our data, the population of eurydendroid cells of masu salmon in cerebellum contains GABA-ergic and PA-ergic cells. Identified in the of masu salmon cerebellum thin nNOS-ip fibers, in our opinion, are the axons of eurydendroid neurons. Thus, nitric oxide, and being located in the projection eurydendroid cells, can acts as a modulator of aspartat-ergic signals in structure of efferent fibres to various parts of the masu salmon brain. Localization of nNOS, NADPH-d and CBS in interfascicular cells of masu salmon, by the classification [48], identified for the first time. We believe that interfascicular CBS-and nNOS-ip neurons of masu salmon are separate subpopulations of cells of the reticular formation, which modulating GABA-and cholinergic system in the medulla oblongata, respectively.
A – clusters of NADPH-d-producing cells (delineated by rectangles) in periventricular area of medulla oblongata of Oncorhynchus masou; on B in a large magnification. C - cystathionine β-synthase (CBS) producing cells (red arrows) in periventricular area of Cyprinus carpio brain, on D in a large magnification. LX – lobus of vagal nerve, IV – forth ventricle, MLF – medial longitudinal fascicle. Scale: А, C – 200 μm, B, D – 50 μm.
Secondary gustatory nucleus is seen as a visceral integrative centre in medulla oblongata in fishes brain [46]. In Carp in this nucleus was found the CBS immunolocalization, and in the masu salmon the secondary gustatory nucleus is CBS-immunonegative, but contains NADPH-d and nNOS. We believe that with the participation of H2S and NO-producing systems in the brain fish is carried out sensory modulation functions related to the evaluation of food in space and coordination of mechanosensor, visual and gustatory features. In Carp brain the main neurotransmitter of the gustatory system is hydrogen sulfide, and in the masu salmon brain is nitric oxide, which confirms the assumption about the use of fish of various signal transductor systems to transfer the neurochemical information in functionally similar complexes.
We have revealed the existence of NO and H2S-producing neurons in brainstem and isthmus regions of masu salmon brain. nNOS-ip and NADPH-d positive neurons were discovered in the composition of somato- and viscerosensoric (V, VII, IX-X) and visceromotoric (III, IV and VI) of craniocerebral nerves, octavo-lateral efferent complex, medial reticular formation. CBS in the medulla of masu salmon was detected in neurons of the nucleus X nerve, reticulospinal cells and ventro-lateral reticular formation. Distribution of NO and H2S-producing neurons in the nuclei of medulla oblongata of masu salmon indicates that NO is the predominant neuromodulator of somato-and viscerosensoric and visceromotoric systems of medulla oblongata, and H2S probably modulates viscerosensoric systems associated with the nucleus X nerve, and descending motor systems. NO and H2S-producing systems in the fishes brain: 1) are independent neural complexes which are carrying out specialized functions in the work of local neural networks; 2) represent separate, non-overlapping systems of intra-and intercellular signaling, modulating the activity of choline-, GABA-and catecholaminergic systems, respectively; 3) regulate the processes of adult neurogenesis in the matrix areas of the brain.
Unlike mammals, the fish brain has a high neuronal plasticity and can produce new cells throughout life [49]. The results of our investigations indicate the existence of nNOS and NADPH-d in neurons and glial cells in the masu salmon brain. It is shown that NO plays the role of signaling agent, regulating the processes directed growth of axons and dendrites and migration of differentiating neurons [50]. It is established that in the subventricular zone of mammalian forebrain is surrounded by NO-producing neurons [51, 52]. Cells expressing nNOS were identified among progenitor cells of dentate girus in the hippocampus of Guinea pig [53]. These areas of the brain are considered zones adult neurogenesis in which the proliferation of the cells is maintained throughout the life of animals and human. The results of our investigation (Fig. 8A, B) suggest that in the periventricular area of the medulla oblongata in masu salmon containing PCNA-ip proliferating cells in different age periods, NO can act as a regulator of adult neurogenesis, which confirms the data obtained on mammals.
Proliferative activity (A and B) and apoptosis (C and D) in the brain of a three-year sturgeon A. schrenckii. PСNA-ip cells are shown triangular arrow, TUNEL labeled elements – are shown black arrows. Scale: A, B-100 μm; C-50 μm; D-200 μm.
In the periventricular area of the medulla oblongata, ventral and lateral areas of the cerebellum of carp are considered matrix areas of the brain of this species [54], identified highly CBS-immunogenic cells, without any processes (Fig. 8C, D). The sizes of cells, their location in the brain and correlations with H2S-producing neurons indicate the presence of H2S-producing of glia in the matrix zone of carp brain. In similar areas of the masu salmon brain such cells were not found. As currently participation of gaseous mediators in the regulation of post-embryonal neurogenesis of mammals was shown [55], we believe that in carp brain H2S can act as such an agent, as the presence of CBS in proliferative areas of brain we consider as one of the proofs of this. One of the mechanisms regulating the in fish producing the large number of cells, educated including postembryonal period is apoptosis [7]. Study of a 60-day old sturgeon fry showed the presence of intensively proliferating zones containing PCNA-ip cells in forebrain. The active proliferation of cells in this period of the sturgeon′s development is complemented by the formation of secondary neurogenetic zones.
Intensity of the processes of proliferation and apoptosis in different parts of the myelencephalon of the Amur sturgeon Acipenser schrenckii. Data are shown as M ± m. A) In the nuclei of trigeminal and facial nerves (NV and NVII, respectively) and perinuclear zones adjacent to these nuclei (PNZ V and PNZ VII, respectively). B) In the lobe of the vagus nerve. PVZ, SVZ, and DZ-periventricular, subventricular, and deep zones, respectively. Ordinate axis-proliferation index, PI (blue columns) and apoptosis index, AI (pink columns), %.
The 3-year olds sturgeons’ zone proliferation and apoptosis in various parts of the intact CNS saved (Fig. 9A, B). The highest proliferative activity was detected in periventricular zone of medulla oblongata, that allows considering this area as a major area of adult neurogenesis (Fig. 14A, 15B). In the medial reticular formation, dorsal nuclei of the thalamus, the inner fibrous layer of tectum opticum and lateral hypothalamus were discovered maximum number of apoptotic elements. This circumstance allows us to suppose that these regions in the sturgeon brain correspond with the areas of postmitotic neuroblasts localization. In the sensory centers (tectum opticum and nuclei V, VII and X nerves were revealed variable ratio processes of proliferation and apoptosis (Fig. 10A), which indicates different rates of growth and differentiation of visual and chemosensory centers of the sturgeon brain. In contrast to mammals in which central divisions of sensory systems are completely formed and correspond strictly to the number of sensory receptors at the moment of birth and/or immediately after this event, sensory projections in the fish brain continue their growth and development during the entire life. Such a peculiarity of the fishes is related to the fact that the CNS organization must adapt to a significant permanent increase in the size of the body and, correspondingly, to a rise in the volume of incoming sensory information. Our studies of projections of the somato- and viscerosensory nuclei of the myelencephalon and tectum opticum of the sturgeon confirmed in general the hypothesis that adult neurogenesis and apoptosis exert significant effects on the peculiarities of postnatal development of the sensory systems. Our findings agree with the published data on intensification of differential growth in primary sensory regions in the lobe of the nucl. vagus of the carp, as well as in the Danio retina and tectum, compared with other cerebral regions [56].
Up to now, it remains unknown whether all types of neurons develop and are integrated into the corresponding networks of the growing brain of fishes. It seems probable that some initial level of organization of neuronal networks in fishes is already preformed at the moment of their hatching, and only some types of neurons continue their formation and integration into existing networks during the later period of life. It is believed that the weak ability for substitution or development of new neurons in the mammalian brain is related to the limited ability of such cells in animals of this class to be integrated into mature neuronal networks [58]. It is hypothesized that neurons formed de novo in adult animals are distinguished by a higher plasticity compared with that of preexisting cells [59, 60]. This viewpoint agrees well with our findings on the sturgeon and allows us to suppose that postembryonic (adult) neurogenesis correlates with coordinated growth of the sensory systems and sensory structures of the brain. Therefore, this phenomenon can open possibilities for the processing of new ontogenetic experience. Incorporation of new cells into the neuronal networks existing earlier in the sensory regions is directly related, first of all, to an increase in the size of the brain in the course of growth of the fish. However, it should be taken into account that fishes, immediately after hatching, possess relatively well preformed sensory and motor systems making possible rather rapid training for complex behavioral habits, e.g., active catching of food and avoidance of predators. This indicates that some parts of the CNS of fishes, which are responsible for information processing and realization of functional needs of the organism necessary within a certain life period, begin to function before hatching. The later postembryonic growth can be considered a process of delayed development related to the maintenance of the functions necessary in future, e.g., for the formation of zoosocial communication or sexual behavior. Therefore, our conclusion that some parts of the sturgeon brain remain, in fact, in the neotenic state over a rather long postembryonic period seems to be quite logical. This hypothesis explains the high indices of proliferative activity in some brain regions in cartilaginous ganoid fishes.
The particular relevance of the results obtained acquire the communications regulatory functions of nitric oxide and hydrogen sulfide, regarded as regulators of adult neurogenesis in the fish brain. We have highlighted nNOS-ip fiber varicose type in subventricular area of the spinal cord, as well as the presence of PCNA-and nNOS-ip cells in the composition of the periventricular area of diencephalon and medulla oblongata in sturgeon and salmon indicates the presence of NO-producing elements in zones containing proliferating cells. On the other hand, detection of NO-ergic activity in TUNEL positive areas of the brain sturgeon indicates the involvement of nitric oxide in the regulation of apoptosis. Thus, it is possible that in the brain sturgeon NO is as proapoptogenic and regulatory proliferation factor exercising to maintain a balance between the two processes. Cytotoxic and neuroprotective effects NO can be viewed as interrelated elements of a single action: if the excess output of NO potentiates the mechanisms of apoptosis in the zones of localization of postmitotic neuroblasts, the factors reducing NO production can be considered as compensatory. In the basis of post embryonic morphogenesis of sturgeon′s A. schrenckii brain, and particular, development of sensor systems are founded on certain ratio of the processes of proliferation and apoptosis, having NO-dependent mechanism of regulation.
Thus, we believe that the peculiarities of the distribution of the investigated systems synthesis of classic neurotransmitters (GABA, catecholamines), as well as gaseous mediators (NO and H2S) is directly linked to the ability of the brain fish grow throughout life. We interpret the obtained results in this context. This led us to the conclusion that some of the classic neurotransmitters (dopamine, GABA), as well as gaseous intermediaries (NO and H2S) are not only regulators of the functional activity of neurons and modulators of synaptic transmission in mature neural networks, but also are considered as inductors of development (morphogenetic factors) in the brain during postembryonic fish ontogenesis. Proof of this is a detection of the phenotypic immature elements in the masou salmon brain adult age, expressing the above mentioned molecules in proliferative areas of the brain, as well as elements that have the morphology of the radial glia. Presence of markers of gaseous intermediaries in the areas of expressing proliferative nuclear antigen (PCNA), proves the involvement of gaseous intermediaries in the regulation of post-embryonal neurogenesis. The fish with the prolonged cycle of development (salmon, and carp) such markers (NO and H2S) in periventricular proliferative areas of the brain may differ, which is consistent with the notion that in functionally similar complexes in animals can be used different signal transduction systems. Development of the nervous system salmon and sturgeon, in contrast to the widespread neurogenetic model D. rerio occurs over a long period of time. According to our data, the different structures of the CNS of masou salmon characterized by severe heterochrony, i.e. the cells of caudal parts of the brain in much earlier than neurons of forebrain departments, acquire the features of phenotypic specialization. We are convinced that the brains of these animals for a long time keeps features of fetal organization, and the presence of first and second years of life low differentiated phenotypically immature cell forms, confirms this hypothesis. The data presented in this study open a new trend in investigation of cellular mechanisms of shaping in structural organization in the postembryonic fishes brain and in examination of morpho-functional manifestations concerning histogenetic processes in different periods of postembrionic ontogenesis. The new priority data received are connected with development of nervous tissue in the pacific salmon brain and with dynamic of the brain shaping and distribution of classical neurotransmitters and gaseous mediators in a context of incessant postembryonic neurogenesis.
This work was supported by the Grant of Far Eastern Branch of Russian Academy of Sciences № 12-III-A-06-095.
The periodontium is a private connective tissue consisting of a gingiva, cementum, periodontal ligament, and alveolar bone supporting the tooth in the socket [1]. Periodontal disease is a widespread, chronic multimicrobial immunoinflammatory illness which began with the complex coaction between the host’s immunoinflammatory responses and pathogenic bacteria in the dental tissue [2]. There are two general forms of periodontal diseases including gingivitis (confined with gingiva form) and periodontitis. Gingivitis is a localized inflammation of the gingiva, which is began by pathogens in the microbial dental plaque on the tooth and gingiva [3]. Gingivitis causes reversible inflammation in the periodontal tissues [3]. Periodontitis, the destructive form of periodontal disease, leads to the destruction of the gingiva, alveolar bone, and periodontal ligament and is responsible for causing tooth mobility and early tooth loss [3, 4]. Periodontitis leads to irreversible local periodontal tissue destruction [5]. Periodontal diseases are the most common chronic diseases impacting 10–15% of population worldwide [6, 7].
Microbial dental plaque, mostly gram-negative anaerobic or facultative pathogens inside the subgingival biofilm, is the principal etiological factor in periodontal diseases [8]. Robust evidence in the etiology of periodontal diseases has been shown responsible for periodontopathogens including Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (PG), Tannerella forsythia (TF), and Treponema denticola (TD) [9]. It is stated that “red complex” pathogens (PG, TD, and TF) are frequent in individuals with periodontitis [10]. The plurality of periodontal tissue devastation is brought about by an unsuitable host response to those pathogens and their products (lipopolysaccharides and proteases) [11]. The coaction between pathogenic bacteria and the host’s immune response is participated by chemokines, the produce of pro-inflammatory cytokines, and an exaggerated immune response, entailing an increase in the number and activity of polymorphonuclear leukocytes (PMNs) [12]. PMNs are the main mediators of host response averse to the bacteria [13].
PMNs create the first advocacy of cellular host defenses averse to pathogenic microorganisms in the gingival sulcus [14]. PMNs defend the host against bacteria in two pathways, including oxygen-dependent and non-oxygen-dependent mechanisms [15]. The oxygen-dependent pathway contains the production of reactive oxygen species (ROS), which causes the destruction of periodontal tissues [16]. Although the main reason for the production of ROS by PMNs is the killing of bacteria, excessive production of ROS in the extracellular space causes the destruction of tissues [8, 14, 16]. The overproduction of ROS leads to tissue damage through different mechanisms including lipid peroxidation, DNA and protein damage, and the stimulation of pro-inflammatory cytokine [1, 16]. Several studies have shown the relationship between ROS and periodontal disease [5, 16, 17, 18]. Oxidative stress (OS), an imbalance between the pro-oxidant and antioxidant system, is involved in the bone resorptive process during periodontal disease [19]. Various studies have shown that OS is involved in the pathophysiological mechanisms of periodontitis [1, 17, 18, 20, 21]. Recently Sreeram et al. have described it as follows: “Periodontitis is an inflammatory condition leading to increased OS” [22].
Antioxidant defense mechanisms (nonenzymatic and enzymatic antioxidants) eliminate ROS and inhibit their detrimental consequences on the host [23]. Antioxidant enzymes protect tissues against the destructive effects of ROS created by different metabolic processes, modulating the dimension of inflammatory response [18, 24]. The defense mechanism averse to ROS involves three antioxidant pathways including intracellular, extracellular, and membrane antioxidants [25]. The main system is intracellular ROS cleaning enzymes: superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) [25]. GSH-Px, as a selenium-containing peroxidase, is a major group of enzymes that eliminate hydrogen peroxide created by SOD in the cytosol and mitochondria by oxidizing reduced glutathione to its oxidized form [22, 26]. GSH-Px is one of the enzymes that has a significant role in host defense averse to oxidative stress in cytosol [1, 18]. GSH-Px1 inhibits cytotoxic peroxide-induced oxidative damage, protein degeneration, and lipid peroxidation [27].
Traditional diagnosis of periodontal disease is based on clinical (gingival index (GI), bleeding on probing (BOP), clinical attachment level (CAL), probing pocket depth (PPD)) and radiographic parameters [22]. Traditional clinical measurements that are used for periodontal diagnosis are frequently of only restricted usefulness inasmuch as they are indicators of previous periodontal disease rather than present disease activity [28, 29]. Knowing the disease activity will enable early detection of the disease [21]. Moreover, the levels of oxidative stress parameters in saliva and gingival crevicular fluid (GCF) may show the activity and severity of periodontal disease [29].
Saliva is used as an easily collected diagnostic fluid that makes it possible to determine the levels of biomarkers in the evaluation of the disease condition [30]. By the way, GCF is a biological fluid in the gingival sulcus that derives from blood plasma and consists of metabolic elements of pathogens and host cells, which are explained as transudates or exudates [31]. Thereby, disease diagnosis via analysis of saliva and GCF is suitable for individuals [21]. Since the half-life of ROS is very short, they cannot be determined easily. Thus, ROS-induced demolition products and the activity of enzymatic and nonenzymatic antioxidants are optimal candidates to assess the consequences of OS-connected events in the pathological process of chronic periodontitis [21]. On the other hand, antioxidants (enzymatic and nonenzymatic antioxidants) in the saliva preserve the unity of oral tissues by neutralizing ROS [14].
In this section, GSH-Px levels are summarized in the periodontal health and disease including the presence and absence of systemic disease, medication, wound healing, smoking.
Wei et al. [32] examined the role of glutathione peroxidase in the pathogenesis of periodontal diseases. They reported higher total amount of GSH-Px in GCF samples from patients with gingivitis and periodontitis compared to healthy subjects [32]. Moreover, they determined that the total amount of GSH-Px was significantly higher in periodontitis patients than in gingivitis patients [32]. Also, there is a positive and significant correlation between the total amount of glutathione peroxidase and interleukin (IL)-1β and plaque index (PI) in GCF of the individuals with periodontal disease [32]. Besides, Panjamurthy et al. [33] assessed the levels of GSH-Px in patients with chronic periodontitis (CP) and determined that GSH-Px activities in the plasma, erythrocyte lysate, and gingival tissues were significantly increased in patients with periodontitis compared to healthy subjects. In addition, Borges et al. [34] analyzed the GSH-Px activities in the gingival tissue of individuals with CP. They determined a significant increase in GSH-Px activities in the individuals with CP when compared to the control group [34]. They noticed that an increase in GSH-Px may indicate possible antioxidant suppression in the destroyed ROS products in the gingival tissue [34]. Moreover, Arunachalam et al. [35] stated that the GSH-Px levels in the plasma of patients with aggressive periodontitis increased compared with the healthy individuals. Conversely, Sreeram et al. [22] and Aziz et al. [36] reported that serum GSH-Px activity in individuals with CP decreased when compared with the control groups.
Tsai et al. [37] aimed to determine the GSH-Px levels in saliva before and after periodontal treatment in patients with CP. They did not find a significant difference in the activities of GSH-Px in saliva between periodontally diseased and healthy subjects and even between prior to and after treatment in periodontitis patients [37]. On the contrary, Çanakçı et al. [20] and Miricescu et al. [38] found that the GSH-Px activities in saliva of patients with periodontitis were significantly lower than the controls. In accordance with Tsai et al. [37], Çanakcı et al. [20] suggested that there were no significant correlations between salivary GSH-Px capacities and periodontal status. Contrary to Tsai et al. [37], Novaković et al. [14, 39] evaluated the GSH-Px activity in saliva of the CP patients before and after nonsurgical treatment and concluded that there was a significant increase in these levels after therapy. Novaković et al. [14] argued that the increase in GSH-Px activity in saliva can be explained by the reduction in periodontal tissue inflammation after nonsurgical therapy. Novaković et al. [39] indicated that salivary GSH-Px could be used as a reliable biomarker in evaluating periodontal status and therapy outcome. A recent meta-analysis declared that there are no significant differences in the salivary GSH-Px levels between the patients with CP and periodontally healthy individuals [21]. These meta-analysis results coincide with other studies that have determined an increase or decrease in salivary GSH-Px levels [21]. The authors claimed that this disagreement might be connected to the various dynamic processes of the periodontitis progression [21].
Almerich-Silla et al. [17] showed the association between GSH-Px levels and the presence of different periodontal pathogens (PG, Aa, TD, and TF). They reported that GSH-Px levels were elevated in the existence of all bacteria types, except PG genotypes III and IV, and also the presence of different types of bacteria has a positive relationship with GSH-Px [17]. The authors advised that determination of GSH-Px levels and periodontal bacteria can be an important tool to control the progression of periodontal disease [17].
Until today, there is contradictory evidence concerning the relationship between the levels of GSH-Px and the periodontal status. Various studies have demonstrated that GSH-Px levels in different biological fluids increased, decreased, or are unaltered in individuals with periodontal disease. This discrepancy might be explained by different determination protocols/assays applied among the studies. On the other hand, a more persuasive change in GSH-Px activity in GCF than in saliva is observed [40]. GCF is more specific for periodontal inflammation than saliva, and also, saliva and serum GSH-Px levels may be affected by systemic conditions.
Replace the entirety of this text with the main body of your chapter. The body is where the author explains experiments, presents and interprets data of one’s research. Authors are free to decide how the main body will be structured. However, you are required to have at least one heading. Please ensure that either British or American English is used consistently in your chapter.
Patel et al. [8] examined the levels of plasma glutathione peroxidase (eGPx) in GCF before and 6–8 weeks after periodontal therapy in patients with periodontal disease. They ascertained that eGPx levels in GCF were significantly elevated progressively from health to gingivitis and periodontitis [8]. The study suggested that increased eGPx level in GCF from inflamed gingiva may indicate the increased ROS generation at the diseased site [8]. Also, the authors determined that the mean concentration of eGPx in GCF in CP group showed a significant reduction after the treatment and thus stated that increased eGPx concentration is associated with the severity of periodontal disease [8]. Similar to the previous study, Patel et al. [41] determined an increase of the eGPx concentrations in GCF and serum progressively from health to gingivitis and periodontitis groups and a decrease of these levels after nonsurgical periodontal therapy. Thus, the authors declared that the increase in GCF and serum eGPx can be considered as a marker of oxidative stress caused by periodontal infection [41]. Moreover, they noted that the significant increase in serum eGPx concentration in the periodontal disease can be possibly because of the overflow from the diseased periodontal tissues or increased production of eGPx by kidney proximal tubules in response to systemic oxidative stress caused by periodontal disease [41].
Sakallıoğlu et al. [25] investigated GSH-Px profiles in the 30-day recovery period (at days 3, 12, 21, and 30) in an acute incisional wound model created with mucoperiosteal periodontal flaps in dogs. They determined that GSH-Px levels increased significantly on the 3rd day of recovery period and then decreased insignificantly on the 12th day and increased insignificantly on the 21st day [25]. Later, GSH-Px levels decreased significantly on the 30th day compared to the 21st day of the recovery period, and these levels are lower than the baseline [25]. It is suggested that GSH-Px plays a significant role in the eradication of ROS in the recovery period of periodontal repair [25]. Moreover they argued that GSH-Px can neutralize to the noxious effects of OH in a normal periodontal mucoperiosteal or gingival wound healing [25].
The etiology of periodontal disease is multifactorial, and periodontal pathogenesis processes are replaced by environmental and acquired risk factors such as smoking [42]. Tobacco smoking is one of the principal modifiable risk factor associated with chronic destructive periodontal disease [36]. It has been reported that the prevalence of periodontitis was three to six times higher in smokers than nonsmokers [16]. Possible negative effects of smoking on periodontal tissues may include altered neutrophil function, decreased IgG production, vascular alterations, increased prevalence of perio-pathogens, altered fibroblast attachment and functions, decreased lymphocyte proliferation, difficulty in eliminating pathogens by mechanical therapy, and negative local effects on cytokinesis and growth factor production [36]. Smoking influences oxidative stress in the body by promoting oxidative burst in neutrophils and causes an imbalance between antioxidants and ROS [43].
Guentsch et al. [16] evaluated both GSH-Px activities in saliva and serum in patients with periodontitis and the effects of periodontal treatment and smoking on these parameters. They reported an elevated GSH-Px activity in saliva in both the nonsmoking and smoking periodontitis groups compared to the periodontally healthy control groups and that these levels, which increased in both periodontitis groups, decreased after treatment [16]. However, the authors did not find a significant difference in serum GSH-Px values of both smokers and nonsmoker individuals with periodontitis and those who are periodontally healthy [16]. It is suggested that elevated GSH-Px levels in the saliva of periodontitis patients indicate to adversely affect antioxidant mechanisms leading to tissue damage of the continuous ROS production in periodontal inflammation [16]. Also, it is shown that smoking increased the GSH-Px levels in patients with periodontitis [16]. On the contrary, Aziz et al. [36] argued that smokers with CP have shown decreased GSH-Px activity in serum when compared to nonsmoker controls.
Hendek et al. [18] examined the effects of initial periodontal therapy on GSH-Px levels in serum, saliva, and GCF samples in smokers and nonsmokers with CP. They found that there was no significant difference among all groups for GSH-Px enzyme activity in serum, while GSH-Px enzyme activity in saliva and GCF was higher in smokers and nonsmokers with CP than periodontally healthy nonsmokers but statistically insignificant in GCF [18]. In addition, authors declared that there was no significant difference in the GSH-Px enzyme activity in GCF, serum, and saliva after periodontal therapy in both periodontitis groups [18]. Their data speculated that elevated GSH-Px activity in periodontitis patients may be a result of tissue repair and adaptive mechanisms against inflamed periodontal tissues in response to oxidative stress [18]. Conversely, Naresh et al. [43] found that the levels of GSH-Px in the saliva of smokers and nonsmokers with CP were decreased when compared with the healthy group and mean GSH-Px levels were lowest in smokers with CP. They stated that exposure to smoking may reduce salivary GSH-Px levels [43].
Toguç et al. [44] investigated the impact of smoking status on the GSH-Px levels in the gingival tissue and blood in subjects with CP. When blood GSH-Px levels are evaluated, the lowest values were observed in the smoker patients with CP compared to nonsmoker patients with CP and in the nonsmoker control group compared to nonsmokers and former smokers with CP [44]. Besides, elevated GSH-Px levels in gingival tissue have been determined in the control group when compared with all CP groups [44]. When gingival tissue GSH-Px levels are evaluated among all CP groups, the lowest values were found surprisingly in nonsmokers [44]. Moreover, they found that there were strong negative correlations between gingival tissue GSH-Px levels and smoking duration and yearly cigarette consumption [44]. Thus, they stated that the reduced local GSH-Px levels in the periodontitis patients may increase with smoking, and the reason for this increase may be the result of a protective and adaptive mechanism developing in the tissue [44].
Periodontal disease has been associated with several systemic illnesses, including atherosclerosis, cardiovascular disease, rheumatoid arthritis, diabetes mellitus, adverse pregnancy outcomes, and Alzheimer’s disease [12].
Diabetes mellitus (DM) is a major risk factor for periodontal diseases, and periodontitis is noted as the sixth complication of DM. It has been shown with increasing evidence that the prevalence, progression, and severity of periodontitis increase in individuals with diabetes, especially uncontrolled, compared to individuals with no diabetes [45, 46]. There is a bilateral relationship between periodontal disease and DM. Various mechanisms have been suggested to clarify this relationship including the formation of advanced glycation end products (AGEs), changes in collagen metabolism and immune function, and recently an increased oxidative stress [47].
Arana et al. [48] evaluated the levels of GSH-Px in the saliva of patients with diabetes mellitus type 2 (DM2) and healthy nondiabetic patients in the presence of periodontal disease. They determined that the salivary GSH-Px levels in the diabetic group with good metabolic control was significantly higher than the control group and the diabetic group with poor metabolic control, and also patients with poor metabolic control in comparison with the control group and well-controlled diabetic groups have worst periodontal health and lowest saliva GPx levels [48]. Authors suggested that poor metabolic control in DM2 patients is associated with lower levels of salivary GSH-Px and worse periodontal health [48]. On the other hand, Duarte et al. [47] evaluated the gene expression of GSH-Px1 in the gingival tissue of poorly and well-controlled type 2 diabetic subjects with CP. They found that the periodontitis groups presented higher expression of GSH-Px1 than the periodontally healthy control [47]. It is advocated that GSH-Px1 was enhanced by periodontitis, independently of the diabetic status of the patients [47].
A recent review has shown a positive relationship between periodontitis and cardiovascular diseases [49]. It is determined that periodontal inflammation increases the development and progression of atheroma plaques via systemic bacteremia and lesion from the interaction of the intima with perio-pathogens entering the circulation [49]. Therefore, it is noted that the presence of periodontitis may be a risk factor for cardiovascular diseases [50]. Moreover, oxidative stress plays an important role in the pathogenesis of both periodontal disease and cardiovascular diseases [51].
Punj et al. [1] investigated the levels of glutathione peroxidase in serum and saliva of CP patients with and without ischemic heart disease (IHD). They stated that salivary GSH-Px levels were increased in the IHD + CP, IHD + H, and CP groups when compared with the healthy controls, whereas the serum GSH-Px levels were increased in the healthy group when compared with IHD + CP, IHD + H, and CP groups [1]. Authors indicated that this situation could probably be a result of a curative increase of GSH-Px to the oxidant stress in diseased states [1]. They emphasized that increased oxidative stress in the presence of chronic periodontitis may cause endothelial dysfunction of the blood vasculature, predisposing to atherosclerotic plaque formation and increasing predisposition to ischemic heart disease [1]. Köse et al. [52] examined the influences of periodontitis on levels of cardiac oxidative stress. Authors found that GSH-Px levels in the heart ventricular tissue of the rats with experimental periodontitis were higher than that of control group but statistically insignificant [52]. They argued that this increase could be associated with adaptive response [52]. Moreover, they speculated that oxidative stress in the cardiac tissue may be the result of an increase in the amount of ROS rather than a decrease in antioxidant levels [52].
Various studies have proven a possible bidirectional association with periodontal disease and pregnancy [53]. It is supported that periodontal diseases are related with adverse pregnancy effects [54]. One of the possible mechanisms underlying this interaction stated that there may be oxidative stress-related inflammation pathways in case of pregnancy and periodontal disease [5, 27]. Oxidative stress is a principal supporting factor in the pathogenesis of preeclampsia and periodontal disease [27]. Çanakçı et al. [40] evaluated the GSH-Px levels in serum, saliva, and GCF in preeclamptic and normotensive pregnant women with and without periodontal disease. They determined that the GSH-Px activities in the serum and GCF of the periodontally healthy normotensive women were higher than that of preeclamptic and normotensive women with periodontal disease and periodontally healthy preeclamptic women [40]. There was no significant differences in saliva GSH-Px activities among all groups [40]. They declared that systemic and local GSH-Px activities reduced with the effect of periodontal disease in addition to the impact of preeclampsia [40]. Similarly Shetty et al. [27] observed that the GSH-Px activity in serum and saliva elevated in normotensive pregnant women with healthy periodontium when compared with preeclampsia pregnant women with and without periodontitis, and also preeclamptic women with periodontitis group have the lowest values but statistically nonsignificant. They indicated that periodontal diseases which cause a reduction in antioxidant levels could be a likelihood risk factor for severity, progression, and even initiation of preeclampsia [27].
Gümüş et al. [5] examined the salivary GSH-Px levels of the pregnant and postpartum women and their link with clinical parameters of periodontal inflammation and disease severity. They assigned that the GSH-Px levels were increased in the postpartum group when compared with pregnant and nonpregnant groups and in the nonpregnant group when compared with pregnant group [5]. Furthermore, they found that salivary GSH-Px levels were positively correlated with PD and BOP and total bacterial numbers in the postpartum group and with PD, CAL, BOP, or PI in the nonpregnant women group [5]. Conversely authors did not find association between GPx levels and periodontal disease status in pregnant women [5]. It is determined that salivary GSH-Px levels, which were at low levels during pregnancy, increased in the postpartum [5]. They speculated that this may be due to a healing mechanism against the exposure of tissues to excessive ROS during pregnancy [5].
Drug-induced gingival enlargement is previously reported as side effect of immunosuppressive agents such as cyclosporine A (CsA) and tacrolimus, calcium channel blockers such as amlodipine and nifedipine, and anticonvulsant drugs such as phenytoin [55]. It has been stated that overgrowth develops due to the increase in collagen accumulation and decrease in collagenase enzyme activity after drug use [55]. Gingival and periodontal inflammation may increase, as excessive gingival enlargement will complicate oral hygiene practices [55]. Sobeniec et al. [56] evaluated the GSH-Px activity in serum and saliva in patients with periodontal disease treated due to epilepsy. They determined that serum and saliva GSH-Px activities decreased in these patients with excessive gingival enlargement when compared with the control group [56]. On the other hand, Sardarian et al. [26], an in vitro study, determined that the low concentration of CsA (0.1 mg/mL) had no effect on GSH-Px activity in the oral epithelium while the activity was significantly increased at higher concentrations (1 mg/mL). They argued that GSH-Px activity increased to eliminate increased ROS in the oral epithelium after treatment with CsA [26].
In an experimental study, rats were infected with multibacterial inoculum containing PG, TD, and TF, as an oral lavage every other week for 12 weeks [12]. Afterward, daily subcutaneous injections of enoxacin, bis-enoxacin, alendronate, or doxycycline were administered for 6 weeks after 6 weeks of multibacterial infection in rats [12]. Subsequently, they evaluated the levels of GSH-Px in the serum of the infected, treated, and sham-infected rats [12]. Consequently, it is determined that serum levels of GSH-Px increased in rats infected with periodontal bacteria when compared with sham-infected rats and reduced in treated rats compared to infected and untreated rats [12]. Authors stated that elevated GSH-Px activity protects the periodontal tissues averse to oxidative stress [12].
Host modulatory therapy (HMT) is a treatment method that aims to decrease tissue destruction and stabilize the periodontium by arranging the components of the host response [57]. HMTs may be categorized as anti-inflammatory drugs, bone-stimulating agents (bisphosphonates), and anti-proteinase agents, such as low-dose doxycycline (LDD) [58]. Caffeic acid phenethyl ester (CAPE) has antioxidant, antitumoral, anti-inflammatory, and immunomodulatory properties and inhibits ROS production during inflammatory processes [59]. Recently, it has been reported that CAPE can modulate the host response [60]. Yiğit et al. [19] evaluated the effects of LDD and CAPE on alveolar bone level and the plasma levels of GSH-Px activity in an experimental periodontitis rat model. They determined that GSH-Px levels in plasma increased in the CAPE + periodontitis group, but decreased in the periodontitis and periodontitis + LDD groups when compared to control group [19]. The authors stated that CAPE significantly increased GSH-Px levels and CAPE may have more antioxidant properties than LDD in periodontal inflammation [19].
A previous study showed the creation of fast reepithelization on the human gingival wounds of the topical application of 1% taurine (2-amino ethane sulfonic acid) [61]. Sree and Sethupathy [62] investigated the effect of taurine as an antioxidant in the management of patients with the chronic periodontitis. For this purpose, they evaluated GSH-Px levels in the plasma and gingival tissue before and after administration of taurine [62]. They reported that decreased GSH-Px levels in plasma and gingival tissue were determined after taurine administration [62]. It is suggested that taurine enhanced the antioxidant status of chronic periodontitis patients by affecting GSH-Px antioxidant levels [62].
While melatonin has a direct neutralizing effect against ROS, it has an indirect effect by increasing the effectiveness of GSH-Px [63]. Özdem et al. [64] investigated the GSH-Px levels in the heart tissues after melatonin application after induction of experimental periodontitis in the rats. They found that the GSH-Px levels in heart tissue were higher in the periodontitis + melatonin group compared to periodontitis + saline solution group and in the healthy + melatonin group compared to healthy + saline solution group, while there were no significant differences between healthy + saline solution and periodontitis + saline solution groups [64]. In line with these results, the authors claimed that application of melatonin caused an increase in GSH-Px levels in the heart tissue either due to its antioxidant properties or by increasing the synthesis of antioxidant enzymes [64]. Furthermore, Kırzıoğlu et al. [24] examined the effects of systemically administered rosuvastatin, which decreases the levels of ROS and increases antioxidant activity, on GSH-Px levels in the serum of the rats with experimental periodontitis. They reported there were no significant differences in the levels of GSH-Px among control, healthy + rosuvastatin, periodontitis, and periodontitis + rosuvastatin groups [24].
There is a growing evidence for the role of ROS in the pathogenesis of periodontal diseases. The short half-life of ROS limits its measurability in biological fluids in the periodontal disease. Therefore, it is stated that it is more reliable to measure the products of ROS-induced tissue damage and levels of antioxidants in the periodontal disease. One of the most frequently detected enzymatic antioxidants in periodontal disease is GSH-Px. Previous studies found that GSH-Px levels in different biological fluids increased, decreased, or are unchanged in individuals with periodontal disease compared to control groups. The reason for this contradiction might be linked to the difference in the analyses applied between studies and the presence of various dynamic processes in progression of periodontal disease. Nevertheless, the common result in the studies stated that GSH-Px protects periodontal tissues against oxidative stress and plays an important role in the progression of periodontal disease. Thus, it was emphasized that GSH-Px can be a reliable biomarker in biological fluids to evaluate periodontal status and results of periodontal treatment. However, further studies in long term using large population are needed in order to better understand how GSH-Px contributes to the development of periodontal diseases using knockout and knockdown techniques.
The authors declare no conflict of interest.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
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\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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