Nature and synthetic zinc ionophores.
\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"8737",leadTitle:null,fullTitle:"Rabies Virus at the Beginning of 21st Century",title:"Rabies Virus at the Beginning of 21st Century",subtitle:null,reviewType:"peer-reviewed",abstract:"Despite significant worldwide progress in fighting rabies, a zoonotic viral disease, it remains an important public health concern, causing approximately 50,000 human cases per year. This book summarizes current knowledge regarding rabies, the prevalence and genetic diversity of the rabies virus, and modern approaches to rabies diagnosis, prevention, and treatment. It is a useful resource for scientists, doctors, and students.",isbn:"978-1-83969-230-7",printIsbn:"978-1-83969-229-1",pdfIsbn:"978-1-83969-231-4",doi:"10.5772/intechopen.80154",price:100,priceEur:109,priceUsd:129,slug:"rabies-virus-at-the-beginning-of-21st-century",numberOfPages:98,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"49cce3f548da548c718c865feb343509",bookSignature:"Sergey Tkachev",publishedDate:"May 11th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/8737.jpg",numberOfDownloads:1303,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:1,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 28th 2020",dateEndSecondStepPublish:"December 1st 2020",dateEndThirdStepPublish:"January 30th 2021",dateEndFourthStepPublish:"April 20th 2021",dateEndFifthStepPublish:"June 19th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev",profilePictureURL:"https://mts.intechopen.com/storage/users/61139/images/system/61139.png",biography:"Dr. Sergey Tkachev is a senior research scientist at the Institute of Fundamental Medicine and Biology, Kazan Federal University, Russia, and at the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Russian Academy of Sciences",institutionURL:null,country:{name:"Russia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1046",title:"Infectious Diseases",slug:"infectious-diseases"}],chapters:[{id:"79919",title:"Introductory Chapter: Rabies in the 21st Century",doi:"10.5772/intechopen.101899",slug:"introductory-chapter-rabies-in-the-21st-century",totalDownloads:31,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Sergey Tkachev",downloadPdfUrl:"/chapter/pdf-download/79919",previewPdfUrl:"/chapter/pdf-preview/79919",authors:[{id:"61139",title:"Dr.",name:"Sergey",surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev"}],corrections:null},{id:"76468",title:"The Early Development of the Vaccinia–Rabies Recombinant Vaccine Raboral®",doi:"10.5772/intechopen.97344",slug:"the-early-development-of-the-vaccinia-rabies-recombinant-vaccine-raboral-",totalDownloads:263,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The recombinant vaccinia–rabies vaccine, now known as Raboral®, has been widely used in Europe and North America to control/eliminate rabies in the principal wildlife vectors, and thus prevent human transmission. The origins of this vaccine are sometimes forgotten, although the formulation has not changed substantially in almost four decades. This groundbreaking vaccine was assembled by a team at a very young (at that time) genetic engineering company, Transgène, in Strasbourg, France. The joint leaders of the rabies vaccine team reflect, 36 years later, on the trials and tribulations that went hand in hand with the construction of the vaccine.",signatures:"Richard Lathe and Marie Paule Kieny",downloadPdfUrl:"/chapter/pdf-download/76468",previewPdfUrl:"/chapter/pdf-preview/76468",authors:[{id:"340277",title:"Prof.",name:"Richard",surname:"Lathe",slug:"richard-lathe",fullName:"Richard Lathe"},{id:"340278",title:"Dr.",name:"Marie-Paule",surname:"Kieny",slug:"marie-paule-kieny",fullName:"Marie-Paule Kieny"}],corrections:null},{id:"76642",title:"The Diagnosis, Clinical Course, Treatment, and Prevention of the Rabies Virus",doi:"10.5772/intechopen.97691",slug:"the-diagnosis-clinical-course-treatment-and-prevention-of-the-rabies-virus",totalDownloads:241,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Rabies, despite available vaccines, causes approximately 55,000 deaths every year. Diagnosing relies on noting physical behaviors such as hydrophobia, vomiting, fever, behavior changes, paralysis, and consciousness, as well as, using several methodologies to molecularly detect the presence of the virus. RABV often enters through a bite wound given that it is transmissible through saliva. Infection spreads from muscle fibers into the peripheral nervous system traveling to the central nervous system. Infection of the central nervous system can lead to encephalitis (furious rabies) or acute flaccid paralysis (paralytic rabies). Treatment relies heavily on the time of exposure. If the patient is diagnosed prior to being symptomatic, post-exposure prophylaxis (PEP) can be administered. However, once the patient has begun displaying symptoms, therapy success rates sharply decline. Prevention includes vaccinating during both pre- and post-exposures, as well as utilizing Stepwise Approach towards Rabies Elimination (SARE) to aid impoverished countries in declining their rabies mortality rates.",signatures:"Jaida Hopkins, Samantha Sweck and Sean Richards",downloadPdfUrl:"/chapter/pdf-download/76642",previewPdfUrl:"/chapter/pdf-preview/76642",authors:[{id:"44936",title:"Dr.",name:"Sean",surname:"Richards",slug:"sean-richards",fullName:"Sean Richards"},{id:"346309",title:"Ms.",name:"Jaida",surname:"Hopkins",slug:"jaida-hopkins",fullName:"Jaida Hopkins"},{id:"346310",title:"BSc.",name:"Samantha",surname:"Sweck",slug:"samantha-sweck",fullName:"Samantha Sweck"}],corrections:null},{id:"76894",title:"Occurrence of Dog Bites and Rabies within Humans in Srinagar, Kashmir",doi:"10.5772/intechopen.98227",slug:"occurrence-of-dog-bites-and-rabies-within-humans-in-srinagar-kashmir",totalDownloads:190,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Open garbage dumps and dog bites are major public health problems in the Kashmir region. In Srinagar city, there are more than 91,000 dogs, or about one dog for every 12 citizens. The mounting street dog population is leading to increasing fright in the city due to the fear of rabies. Although treatable, rabies can be deadly without access to vaccines and treatment. Unfortunately, Kashmir is experiencing a shortage of the anti-rabies vaccine. More than 80,000 dog bites and 20 deaths due to rabies were reported in the Kashmir valley in the period 2008–2012. We conducted our study of dog bites in Srinagar, which has a large stray dog population, perhaps due to mismanagement of garbage. We obtained our data from Shri Maharaja Hari Singh (SMHS) Hospital. We found that most dog bite victims were males aged 30–40 years presenting with category 3 bites to the legs. The majority of victims were bitten in the evening and reported to the hospital the same day. Most victims received immunoglobin treatment. We suggest that proper garbage control can help to curb the stray dog population in the area and thus reduce the incidence of rabies.",signatures:"Namera Thahaby, Afzal Hoque Akand, Abdul Hai Bhat, Shabeer Ahmed Hamdani and Mudasir Ali Rather",downloadPdfUrl:"/chapter/pdf-download/76894",previewPdfUrl:"/chapter/pdf-preview/76894",authors:[{id:"339059",title:"Dr.",name:"Namera",surname:"Thahaby",slug:"namera-thahaby",fullName:"Namera Thahaby"},{id:"348665",title:"Dr.",name:"Afzal",surname:"Hoque Akand",slug:"afzal-hoque-akand",fullName:"Afzal Hoque Akand"},{id:"348666",title:"Dr.",name:"Shabeer",surname:"Ahmed Hamdani",slug:"shabeer-ahmed-hamdani",fullName:"Shabeer Ahmed Hamdani"},{id:"348667",title:"Dr.",name:"Abdul",surname:"Hai Bhat",slug:"abdul-hai-bhat",fullName:"Abdul Hai Bhat"},{id:"417258",title:"Prof.",name:"Mudasir",surname:"Ali Rather",slug:"mudasir-ali-rather",fullName:"Mudasir Ali Rather"}],corrections:[{id:"81456",title:"Corrigendum to: Occurrence of Dog Bites and Rabies within Humans in Srinagar, Kashmir",doi:null,slug:"corrigendum-to-occurrence-of-dog-bites-and-rabies-within-humans-in-srinagar-kashmir",totalDownloads:null,totalCrossrefCites:null,correctionPdfUrl:null}]},{id:"77118",title:"Rabies Virus Infection in Livestock",doi:"10.5772/intechopen.98228",slug:"rabies-virus-infection-in-livestock",totalDownloads:444,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Rabies is a lethal zoonotic encephalomyelitis and a major challenge to public and animal health. Livestock are affected by rabies mostly through bites of rapid dogs or wildlife carnivore\\'s species. They are considered as ‘dead-end’ hosts that do not transmit the virus. Rabies in livestock has been endemic in many developing countries for many years and diagnosed through clinical signs and dog-biting history. An introduction on rabies situation in farm animals will be given then subchapters including `rabies in bovines, rabies in small ruminants, rabies in swine and rabies in camelids. In each subchapter we shall discuss, epidemiology, modes of transmission, diagnosis and prevention and control measures.",signatures:"Abdelmalik I. Khalafalla and Yahia H. Ali",downloadPdfUrl:"/chapter/pdf-download/77118",previewPdfUrl:"/chapter/pdf-preview/77118",authors:[{id:"339195",title:"Prof.",name:"Abdelmalik I.",surname:"Khalafalla",slug:"abdelmalik-i.-khalafalla",fullName:"Abdelmalik I. Khalafalla"},{id:"339196",title:"Prof.",name:"Yahia H.",surname:"Ali",slug:"yahia-h.-ali",fullName:"Yahia H. Ali"}],corrections:null},{id:"78534",title:"Rabies Virus in Sierra Leone: Challenges and Recommended Solutions for Elimination by 2030",doi:"10.5772/intechopen.99691",slug:"rabies-virus-in-sierra-leone-challenges-and-recommended-solutions-for-elimination-by-2030",totalDownloads:134,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The objective of this write-up is to find possible solution control canine rabies virus in Sierra Leone and other low-income countries in the world. Rabies is a viral disease affecting both humans and animals in Sierra Leone. The country has no policy on dog ownership and management, two veterinarians, limited access to rabies vaccines and human immunoglobin, and a lack of information about the disease in the country despite increasing dog bite cases and death. There is no wildlife specialist to initiate wildlife vaccination. Continuous vaccination increased awareness, trained personnel in veterinary and wildlife, development of policies on responsible dog ownership and by-laws and increase financial support from the government and private sector will help Sierra Leone eliminate rabies in the first half of the twenty-first century.",signatures:"Roland Suluku, Emikpe Benjamin Obukowho, Abu Macavoray and Moinina Nelphson Kallon",downloadPdfUrl:"/chapter/pdf-download/78534",previewPdfUrl:"/chapter/pdf-preview/78534",authors:[{id:"267849",title:"Ph.D. Student",name:"Roland",surname:"Suluku",slug:"roland-suluku",fullName:"Roland Suluku"},{id:"339758",title:"Prof.",name:"Benjamin",surname:"Emikpe",slug:"benjamin-emikpe",fullName:"Benjamin Emikpe"},{id:"339759",title:"Mr.",name:"Abu",surname:"Macavoray",slug:"abu-macavoray",fullName:"Abu Macavoray"},{id:"339760",title:"Mr.",name:"Moinina Nelphson",surname:"Kallon",slug:"moinina-nelphson-kallon",fullName:"Moinina Nelphson Kallon"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:{id:"19",series:{id:"13",title:"Veterinary Medicine and Science",issn:"2632-0517",editor:{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}}}},tags:null},relatedBooks:[{type:"book",id:"3310",title:"Encephalitis",subtitle:null,isOpenForSubmission:!1,hash:"628dc11c26c442f1d4667cccef7762e7",slug:"encephalitis",bookSignature:"Sergey Tkachev",coverURL:"https://cdn.intechopen.com/books/images_new/3310.jpg",editedByType:"Edited by",editors:[{id:"61139",title:"Dr.",name:"Sergey",surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,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"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"825",title:"Current Topics in Tropical Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ef65e8eb7a2ada65f2bc939aa73009e3",slug:"current-topics-in-tropical-medicine",bookSignature:"Alfonso J. 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Gaze"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},onlineFirst:{chapter:{type:"chapter",id:"80582",title:"Role of Zinc and Zinc Ionophores in Brain Health and Depression Especially during the COVID-19 Pandemic",doi:"10.5772/intechopen.102923",slug:"role-of-zinc-and-zinc-ionophores-in-brain-health-and-depression-especially-during-the-covid-19-pande",body:'Zinc is a trace metal ion that has a role in both physiological and pathological processes, making it one of the most common and necessary components involved in brain function. The cortex, amygdala, olfactory bulb, and hippocampus neurons all carry “free ionic zinc” (Zn2+), which appears to have the largest concentration of zinc in the brain. Zinc is involved in the physiochemical function of enzymes, proteins, and signal transcription factors, as well as the maintenance of numerous homeostatic systems, functioning as structural, regulatory, and catalytic cofactors for enzymes including DNA and RNA polymerases, histone deacetylases, and DNA ligases. Zinc is also required for cell proliferation and genomic integrity [1, 2, 3, 4, 5].
As a neuromodulator, zinc is produced during synaptic transmission and attaches to presynaptic or postsynaptic membrane receptors, allowing it to translocate from presynaptic terminals to postsynaptic neurons [6, 7]. Zinc can be found in glutamatergic neurons’ synaptic vesicles. Zinc is therefore liberated from glutamatergic synaptic vesicles and then interacts with excitatory and inhibitory amino acid receptors (N-methyl-D aspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and γ-aminobutyric acid (GABA) [8, 9, 10]. Because of its actions on numerous voltage-gated ion channels, extracellular Zn2+ can modify the excitability of nerve cells [11, 12, 13].
Besides, zinc is required for cell proliferation control in a variety of mechanisms, including hormonal regulation of cell division. Also, zinc serves as a biochemical signal to immune cells and transcription factors involved in the synthesis of inflammatory cytokines. Zinc supplementation has been proven in trials to reduce rates of infection and proinflammatory cytokine secretion. Zinc also possesses metal-binding characteristics and is widely recognized for its antioxidant qualities [14, 15]. Zinc deficiency causes apoptosis in neurons via the mitochondrial pathway [16, 17]. Zinc has just lately been discovered to have a role in intracellular signaling as a second messenger. It is also used by immune cells as a molecular signal. Zinc controls a variety of transcription factors that control gene expression and are engaged in the signal transduction of inflammatory cytokines and adhesion molecules. Zinc helps to preserve genomic stability by regulating redox homeostasis, DNA repair, synthesis, and methylation [18, 19].
Zinc has a variety of crucial roles in neurogenesis [4]. Zinc deficiency decreases the neurogenesis process and impairs the expression of genes involved in hippocampus proliferation and neuronal development in the postnatal rat cerebellum [20]. Further, zinc deficiency reduces the proliferation of the human neuroblastoma cell line, promotes apoptosis, and inhibits retinoic-acid-induced neuronal development in cultured cells [1, 21].
Of note, zinc is found in the presynaptic glutamatergic vesicles across the brain, including the cerebral cortex, limbic system, hippocampus, and olfactory bulb [22].
It acts as a neuromodulator on a wide range of membrane receptors, ion channels, and transporters [23]. Synaptic zinc, in particular, is enhanced via a specialized zinc transporter, ZnT3, and is coreleased with glutamate during action potential-induced exocytosis [24]. These also have an impact on synaptic transmission, which interacts with receptors and channels that regulate auditory processing [25, 26]. Synaptic zinc has been discovered to inhibit NMDA receptors, GABA-A receptors, and calcium channels while activating AMPA and glycine receptors [27, 28, 29, 30]. Zinc also has vital effects on other kinds of receptors, including serotonin, dopamine, and acetylcholine receptors, as well as voltage-gated ion channels for sodium, potassium, calcium, and chlorine [29, 31].
Synaptic zinc regulates sensory processing and improves acuity in the discrimination of different sensory stimuli. Synaptic zinc plasticity leads to prolonged adaptations and sense memories. Recently, the mechanism of this long-term synaptic zinc plasticity has been described as being due to group 1 metabotropic glutamate receptors (G1 mGluRs)-dependent mechanism that triggers a bidirectional long-term change in synaptic zinc signaling [32].
No one denies that depression treatment is a gateway to overcoming many social and psychological problems that affect millions of people all over the world. Many factors play a role in depressive-like behaviors, such as impairment of functions of the hippocampus and the prefrontal cortex. These brain parts play an important role in decision-making processes, so any dysfunction at this area can induce a predisposition to negative feelings, and many glucocorticoid receptors are involved in these areas [33].
In terms of both pharmacological and clinical/epidemiological data, recent years have provided additional evidence confirming the role of zinc in depression. Zinc demonstrated antidepressant-like efficacy in preclinical studies and depressive models. Clinical evidence suggested that zinc supplementation might be beneficial in people suffering from depression. Zinc supplementation has been demonstrated to be beneficial as adjuvant therapy or as a stand-alone intervention for depression. Furthermore, zinc consumption has been linked to an increased risk of depression. Dietary zinc restriction was found to be a causal factor in the development of depressive-like symptoms or anhedonia in mouse studies [34]. Some epidemiological studies have reported that reduced nutritional zinc consumption is related to depression in females but not in males [35]. Even though the first prospective study examining the relationship between zinc intake and depression risk found a small but significant inverse correlation between them, a 20-year follow-up study found that a reduced dietary zinc intake protects from depression in men who were not previously depressed. However, because the research participants were all men with a hospital discharge diagnosis of unipolar depression, the findings cannot be applied to women or patients who did not require hospitalization. On the contrary, a reduced nutritional zinc intake was found to be a risk factor for depression in a prospective analysis of both men and women [36]. Mice missing the G-protein-coupled receptor 39 (GPR39), a zinc-activated receptor, show depressive-like behavior [37]. TC-G-1008, a GPR39 agonist, was recently discovered to have antidepressant-like effects [38]. These findings add to the growing body of evidence that zinc is useful in the treatment of depression.
Meta-analyses support the use of zinc as a supplement in the treatment of severe depression, and single research currently supports the use of zinc for psychotic symptoms [39]. Zinc deficiency has also been linked to neuropsychiatric symptoms such as altered behavior and cognition, learning difficulties, and depression [40, 41, 42].
The link between zinc dysregulation and psychiatric disorder was that zinc acts as an inhibitory modulator at the NMDA glutamate receptor [43, 44, 45]. In addition, the inhibitory effects on the nicotinic acetylcholine receptor (nAChR), GSK3 (glycogen synthase kinase 3beta), and NOS (nitric oxide synthase) are also relevant to depressive processes [46, 47].
Numerous studies show lower zinc blood levels in depressed people compared with healthy people, with a meta-analysis showing depressive symptomatology at zinc serum levels of 1.8 M or below [48]. In several investigations, zinc supplementation enhanced mood in those who were suffering from treatment-resistant depression [41, 49].
Zinc’s effect on the brain-derived neurotrophic factor (BDNF), a growth factor that promotes neurogenesis and differentiation, may be connected to depression. The hippocampus is a center of lifelong neurogenesis, and periods of significant depression are associated with reduced BDNF expression and neuro/synaptogenesis. Rodents on a zinc-deficient diet had lower zinc levels in the hippocampus vesicles, a part of the brain where zinc levels are generally greater, as well as lower amounts of progenitor cells and immature neurons. Zinc-rich diets, on the other hand, increased amounts of progenitor cells [3, 41]. The GPR39 receptor is most likely a critical connection in the interaction between zinc and the serotonergic system, which is required for antidepressants that affect the serotonin pathway to work [34].
Of note, laboratory animal models showed that zinc insufficiency induces thymus and lymphoid tissue atrophy. It lowers the number of spleen cells and the sensitivity to antigens that are both T-cell-dependent and -independent [50]. Microglia is a kind of immune cell found in the central nervous system (CNS) [51]. The link between zinc and microglial activation reflects an undiscovered process that may play a role in neuropathy. However, zinc is produced by neurons under several conditions to activate microglial [52].
Ionophores are ion carrier molecules that reversibly bind and transport ions through biological membranes. Many ionophores are lipid-soluble ion transporters that traverse the cell membrane. Ionophores accelerate ion transport through hydrophobic membranes such as liquid polymeric membranes (carrier-based ion-selective electrodes), lipid bilayers in live cells, or synthetic vesicles (liposomes). A hydrophilic core and a hydrophobic section interact with the membrane in the structure of an ionophore [53]. Many microorganisms, fungi, and plants naturally manufacture ionophores, which import ions into their cells and function as a defense against competing or harmful species. Ionophores made from synthetic materials have also been developed. Ionophores that select for cations and anions have a wide range of uses in the analysis [54]. When paired with the ion they bind, these chemicals have been proven to have a variety of biological effects as well as a synergistic impact [55]. Ionophores change the permeability of biological membranes in the direction of certain ions for which they have affinity and selectivity (Figure 1). An ionophore has a hydrophilic core and a hydrophobic section that interacts with the membrane in terms of structure. An ionophore-ion complex is formed when ions are bound to the hydrophilic center. X-ray crystallography has confirmed the structure of the ionophore-ion complex [58].
Zinc ionophores mechanism in penetrating cell membranes. Two ionophore molecules can mediate intracellular zinc accumulation by exchanging extracellular Zn2+ with 2H+ [
Zinc ionophores (Table 1; Figure 2) have been shown to inhibit replication of various viruses in vitro, including coxsackievirus [63, 65], equine arteritis virus [68], coronavirus [68], HCV [69], HSV [70], HCoV-229E [71], HIV [72, 73], mengovirus [63, 65], MERS-CoV [71], rhinovirus [65], SARS-CoV-1 [68], and Zika virus [74].
Zinc Ionophore | Sources | References |
---|---|---|
Calcimycin | [59, 60] | |
Chloroquine | [61] | |
Clioquinol | Synthetic ionophore | [55] |
Diiodohydroxyquinoline | Synthetic ionophore | [62] |
Dithiocarbamates | Synthetic ionophore | [63] |
EGCG | [64] | |
Hinokitiol | [65] | |
Proanthocyanidins | Grape seed | [66] |
PBT2 | Synthetic analog of 8-hydroxyquinoline | [67] |
Pyrithione | [65] | |
Quercetin | Vegetables, fruits, berries, herbs, trees, and other plants | [64] |
Zincophorin | [55] |
Nature and synthetic zinc ionophores.
Natural zinc ionophores and their sources. Chemical structures of ionophores obtained from Pubchem database (Hinokitiol, CID: 3611; quercetin, CID: 5280343; EGCG, CID: 65064; Proanthocyanidin, CID: 108065).
Quercetin has attracted the attention of many researchers because of its capacity to pass the blood–brain barrier. It appears in the brain after hours of administration and plays a key function in the central nervous system [75]. Discoveries from animal model research reported that antioxidant, anti-inflammatory, and neuroprotective effects of quercetin keep neurons in healthy condition by inhibiting the formation of hydroperoxide, reducing free radicals, and restoring antioxidant enzymes. Further, the study of quercetin at rat models proves its antidepressant action [76, 77]. Also, quercetin can reduce stress and depressive-like symptoms [75].
EGCG may act as a new antidepressant by inhibiting neuroinflammation, which may help to alleviate depression. Models of chronic unexpected mild stress (CUMS) in rats have been created in experimental investigations of depression [78]. Although the etiology of depression is not well understood, one popular theory is that depressed people have greater amounts of cytokines such as IL-6 due to lower levels of amines such as serotonin, noradrenaline, and dopamine [79]. EGCG injection improved depressed behavior in rats by reducing Il-6 levels in the hippocampus. As a result, EGCG was suggested to be used as a new antidepressant to reduce neuroinflammation, which could help to alleviate depression [80].
Hinokitiol (β-thujaplicin) is a monoterpenoid that occurs naturally in the wood of Cupressaceae plants. It is a natural zinc ionophore that is safe to use. Because of its powerful, broad-spectrum antiviral, antibacterial, antifungal, anti-inflammatory, and anticancer effects, it is frequently employed in oral care and medicinal products. It is also a food additive that does not build up in the body. Throughout years of use, there have been no reports of allergic, poisonous, or adverse consequences in the literature. Hinokitiol is a safe zinc ionophore that increases the intracellular pool of labile zinc by facilitating zinc influx into cells [81].
Proanthocyanidins (GSPs), which comprise dimers, trimers, oligomers, and oligomers of catechin and epicatechin, are known to have antidepressant properties. Recent research has demonstrated the mechanism of GSPs’ antidepressant effects in female juvenile prenatally stressed offspring rats. The main pathway was that GSPs work synergistically to inhibit oxidative stress and inflammatory response activator proteins [66].
High rates of neuropsychiatric symptoms (e.g., depression) have been observed among patients affected by COVID-19, suggesting an effect of COVID-19 on the human central nervous system (CNS) [82, 83, 84, 85]. It was showed globally that depression is a leading cause of disability [86]. Accordingly, clinically significant depression and depressive symptoms in post-COVID-19 syndrome may have severe implications as it relates to life outcomes quality [86]. Herein according to previous research studies, we showed zinc deficiency as a possible risk factor for depression symptoms, which were commonly observed following severe infection of COVID-19. A meta-analysis of 17 observational studies found that blood Zn2+ concentrations were lower in depressed subjects than in control subjects [48]. Interestingly, a recent study showed that a significant number of patients with COVID-19 were zinc-deficient [87], and a higher number of zinc-deficient COVID-19 patients had prolonged hospital stay when compared with those with normal zinc levels and required intensive care unit (ICU) [87]. A significant positive correlation was observed between the prevalence of zinc deficiency and COVID-19 cases [88]. A pooled analysis of 1532 COVID-19 patients suggested that zinc deficiency was associated with a sixfold increased risk of severe disease and 16-fold increased risk of death via elevating LDH [89] The elevated LDH in the present study was probably indicative of severe disease [87].Because zinc has a critical role in regulating functions of the human brain, many disorders have been linked with Zn2+ deficiency, including neurological diseases, such as psychiatric disorders, (depression) [48, 89] and schizophrenia [90]. Consequently, the clinical picture, which is common in severe COVID-19 patients and is referred to as “Depression” [82, 83, 84, 85], is nothing more than depression seen in zinc deficiency [48, 87, 88, 89]. Most likely, depression and other mental problems in these patients also develop due to zinc deficiency in nerve cells in the brain.
The first study revealing a relationship between depression and dietary zinc deficiency was conducted by Amani et al. [90]. This study included 23 young females diagnosed with moderate and severe depression and 23 healthy volunteers who were age-matched. The findings revealed that the depressive group’s daily zinc consumption and serum zinc concentration were both lower than the healthy women’s. Moreover, an inverse correlation between serum zinc concentration and the depression scores was obtained [90]. According to the World Health Organization (WHO), zinc deficiency affects at least one-third of the world’s population [91]. The fact that zinc deficiency is linked to the risk of infection and severe advancement of COVID-19 [91] gives a first significant clue on a link between zinc deficiency and the risk of infection as well as its symptoms with unknown etiology such as depression and suggests possible benefits of zinc supplementation. Owing to Zn2+ neuroprotective properties, it is not surprising that Zn2+ supplementation could be effective not only on COVID-19-related symptoms but also on virus replication, as well as on COVID-19-related inflammation and neurological damage [92]. In vitro, Zn2+ inhibits Coronavirus and Arter virus RNA polymerase activity, and zinc ionophores prevent these viruses from replicating in cell culture [93]. Zinc ionophore may play a role in therapeutic management for COVID-19 [94].
Zinc deficiency has been linked to different nervous system disorders. Because zinc is not fat-soluble, it requires transporters called zinc ionophores, which facilitate the entrance of zinc in cytoplasm increasing its level of concentration in the body after consumption. The role of zinc in protecting brain cells has been extensively studied recently particularly in depression treatment. Therefore, natural zinc ionophores plus zinc supplements, which are commercially available, could be a new way to treatment of many neuropsychiatric disorders. Zinc ionophore may play a role in therapeutic management for COVID-19 and postcovid-19 depression.
AMPA | α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid |
BDNF | brain-derived neurotrophic factor |
CUMS | chronic unexpected mild stress |
EGCG | Epigallocatechin gallate |
G1 mGluRs | group 1 metabotropic glutamate receptors |
GABA | γ-aminobutyric acid, gamma-Aminobutyric acid |
GPR39 | G-protein coupled receptor 39 |
GSK3 | glycogen synthase kinase 3beta |
GSPs | Proanthocyanidins |
nAChR | nicotinic acetylcholine receptor |
NMDA | N-methyl-D aspartic acid |
NOS | nitric oxide synthase |
LDH | Lactate dehydrogenase |
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
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\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
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