\r\n\tThis book chapter’s main theme will be focused on transmission dynamics, pathogenesis, mechanisms of host interaction and response, epigenetics and markers, molecular diagnosis, RNA interacting proteins, RNA binding proteins, advanced development of tools for diagnosis, possible development of concepts for vaccines and anti drugs for RNA viruses, immunological mechanisms, treatment, prevention and control. \r\n\t
",isbn:"978-1-80355-667-3",printIsbn:"978-1-80355-666-6",pdfIsbn:"978-1-80355-668-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"52f8a3a1486912beae40b34ac557fed3",bookSignature:"Ph.D. Yogendra Shah",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg",keywords:"HIV, Dengue, Zika, West Nile Virus, Chikungunya, Rabies, SARS-CoV2, MERS-CoV, Hanta Virus, Influenza, Whole Genome Sequencing, DNA Sequencing",numberOfDownloads:168,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 4th 2021",dateEndSecondStepPublish:"November 1st 2021",dateEndThirdStepPublish:"December 31st 2021",dateEndFourthStepPublish:"March 21st 2022",dateEndFifthStepPublish:"May 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"8 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Shah obtained his Ph.D. degree in Veterinary Medicine from Hokkaido University, Japan. He was awarded the Young Science and Technology Award from the Nepal Academy of Science and Technology (NAST) in 2019. His research interests include infectious diseases, zoonotic infectious diseases, and vector-borne diseases.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah",profilePictureURL:"https://mts.intechopen.com/storage/users/278914/images/system/278914.jpg",biography:"Dr. Yogendra Shah is a consultant microbiologist/virologist, senior research microbiologist, and lecturer at Seti Provincial Hospital, COVID-19 PCR laboratory, National Zoonoses and Food Hygiene Research Center, and Kathmandu College of Science and Technology, Nepal. He obtained a Ph.D. in Veterinary Medicine (Bacteriology) from the Graduate School of Veterinary Medicine, Hokkaido University, Japan, in 2017. His research focuses on better understanding the molecular epidemiological features/transmission dynamics of infectious diseases and zoonotic infectious diseases in Nepal by employing molecular techniques like ELISA, polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and DNA sequencing. He was awarded the Young Science and Technology Award from the Nepal Academy of Science and Technology (NAST) in 2019. His research interests include infectious diseases, zoonotic infectious diseases, and vector-borne diseases. 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1. Introduction
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The peripheral nervous system (PNS) is very complex, being composed of the cranial nerves and the spinal nerves, which project from the spinal cord and pass through the intervertebral foramina of the vertebrae [1]. Peripheral nerves, composed of motor and sensory neurons, are considered as complex organs and are present in nearly all parts of the human body [2]. Motor neurons transmit processed information from the central nervous systems (CNS) to skeletal muscles via efferent pathways, whereas collected information from periphery travels to the brain via afferent pathways, after they are translated into nerve signals [3]. Neurons are the main cells of the PNS, but there are two kinds of neuroglia in the PNS, namely Schwann cells and satellite cells. Neurons are made up of the body (soma) and their thin processes of the cell, which are called dendrites and axons. In the soma of the neuron, there are many types of organelles [4]. Based on the number of extensions that arise from the cell body, neurons can be multipolar (three or more extensions), bipolar (two extensions, one axon and one dendrite) or unipolar (only one extension), which are very short and divided in the form of a letter T [5].
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Peripheral nerve injuries (PNIs) are very common, and automobile accidents are the most common cause of nerve trauma [6], with most cases (75%) occurring in the upper limbs [7]. However, the etiological factors of PNI are different in peace and conflict periods, and, historically, most knowledge of PNIs was developed during wars [8]. Nerve injuries can be caused by lacerations with sharp objects, penetrating trauma, stretching or crushing trauma, fractures and wounds [9]. Lacerations, especially those which were caused by a knife blade, are another common cause of PNIs, comprising 30% of serious injuries in some series [10]. Compression is another common cause of PNIs, including ‘Saturday Night Palsy’ caused by radial nerve compression, which causes entrapment neuropathies [11]. The most severe form of nerve injury is a transection, which is known as grade V neurotmesis, usually owing to a laceration from a knife, firearm or glass shard [12]. The neurotmesis is characterised with a full transection of the axons and connective tissue layers wherein complete discontinuity of the nerve is observed [13]. There are numerous classifications of nerve injuries, but of these classifications, the most widely accepted are those developed by Seddon and Sunderland [14, 15].
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After a peripheral nerve sustains a traumatic injury, complex pathophysiologic changes, such as morphologic and metabolic changes, occur at the injury site [16]. Furthermore, these complex changes occur in the nerve cell body, in the proximal and distal segments to the injury site, as well as in the distal endings of both muscle end‐plates and sensory receptors [17]. These changes are characterised by axonal degeneration, which follows a sequence of events within the zone of trauma extending both proximally and distally [18]. Disconnected axons and cell bodies (in proximal axon injuries) degenerate via chromatolysis [19]. The degenerative changes in the distal segment were first described by Waller in 1850 based on observations of frog glossopharyngeal and hypoglossal nerves after injury [20]. Wallerian degeneration starts almost immediately after axotomy and lasts for 3–6 weeks [17].
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The regenerative process begins almost immediately after nerve injury. The first wave of axonal sprouting occurs within hours of axotomy [21]. Two days after this first wave of axonal sprouting, a second wave of this process of regeneration starts [22]. According to some authors, axons may branch once they reach the distal stump, and in these cases, one axon may give rise to several branches [23]. It is known that Schwann cells play an important role in nerve regeneration at the site of nerve injury because they elaborate processes that include physical conduits that lead axons to their targets [17]. The extension of Schwann cells’ processes can limit the rate of axon regeneration more than axonal growth [24]. Regeneration of the damaged peripheral nerve depends on the microsurgical procedure performed. Currently, there are several operating techniques that can be used to repair injured nerves, such as direct epineural repair, grouped fascicular repair, fascicular repair and nerve grafting [25]. However, there are some factors that influence the regeneration process after nerve repair, such as the nature, location and extent of damage, the extent and timing of repair, fascicular anatomy and patient factors (age, physical condition, metabolic disorders, avitaminosis and the presence of any disease).
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In addition, recently some experimental studies have shown that nerve regeneration after its repair can be improved by some pharmaceutical agents, mainly used locally at the site of nerve repair. Drugs commonly used for this purpose include tacrolimus [26–29], hyaluronic acid and its derivatives [30–32], melatonin [33–35], methylprednisolone [36–39], vitamin B complex and vitamin B12, [40–42], calcium and potassium channel blockers [43, 44] and riluzole [45, 46]. These substances have neuroprotective and neuroregenerative properties, though different mechanisms contribute markedly to nerve regeneration.
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Therefore, the main aim of this chapter is to present new insights into the mechanisms of action of many of the above‐mentioned pharmacological agents on the prevention of perineural scar formation and on nerve regeneration after peripheral nerve surgery. However, it is understandable that complete regeneration and functional recovery will almost never be achieved, regardless of the operative technique used or the type of pharmacological agent applied.
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2. Hyaluronic acid
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Hyaluronic acid (HA) (CAS No. 9004‐61‐9) is a natural glycosaminoglycan formed by bonding N‐acetyl‐d‐glucosamine with glucuronic acid [47]. It is a mucopolysaccharide, which occurs naturally in all living organisms, and is several thousands of sugars (carbohydrates) long. Disaccharide units are formed at the plasma membrane in vertebrates and some bacteria [48, 49]. HA is characterised by a very large number of disaccharide pairs (10,000 or more), so its molecular mass is approximately 4 million Da [50]. HA was discovered in bovine vitreous humour by Meyer and Palmer in 1934. These authors found that the HA contained two sugar molecules, one of which was uronic acid, and they proposed the name ‘hyaluronic acid’ [51], while the term ‘hyaluronan’ was introduced in 1986 by Endre Balazs to conform with the international nomenclature of polysaccharides [52]. HA is a major primary component in the extracellular matrix, but it has also been found intracellularly. HA has been isolated from many other sources, and its physicochemical structural properties and biological role have been studied in numerous laboratories [53]. The biosynthesis of HA has been studied for over six decades, but our understanding of the biochemical details of HA assembly is still incomplete. The enzyme responsible, HA synthase (HAS), is a membrane protein that requires only Mg2+ and two sugar‐UDP substrates (GlcUA‐UDP and GlcNAc‐UDP) to polymerise HA chains [54]. In 1993, the hasA gene was identified and cloned, and the HAS protein from Streptococcus pyogenes was expressed [55, 56]. It was also demonstrated that only the HAS protein was required to synthesise HA [57]. It is known that mammalian genomes have three different HAS genes (HAS1, HAS2 and HAS3) that are expressed at specific times and in specific tissues during development, ageing and wound healing, as well as under normal and some pathologic conditions [58, 59].
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HA has numerous biological functions, such as maintenance of the elastoviscosity of liquid connective tissues, for example, in joint synovial and eye vitreous fluid, control of tissue hydration and water transport, as well as supramolecular assembly of proteoglycans in the extracellular matrix. Furthermore, HA has various receptor‐mediated roles in cell detachment, mitosis, migration, tumour development and metastasis, and inflammation [52, 60]. The predominant role of HA in organisms is unknown, but some clinical studies have demonstrated various physiological effects of exogenous HA. Exogenous HA enhances chondrocyte HA and proteoglycan synthesis, reduces the reproduction and activity of proinflammatory mediators, such as matrix metalloproteinases, and alters the behaviour of immune cells [61]. HA has also been successfully used in peripheral nerve surgery to reduce nerve adhesions during wound healing after nerve injury, which occur during ophthalmological, cardiovascular and dermatological procedures, including supplementing joint fluid in arthritis [32, 62, 63]. HA is known to reduce the extent of scar formation and nerve adhesions via the inhibition of lymphocyte migration, proliferation and chemotaxis of granulocyte phagocytosis and degranulation, and macrophage motility in order improve peripheral nerve regeneration [31, 64]. These functions are manifested during scavenging of reactive oxygen‐derived free radicals, the inhibition of immune complex adherence to polymorphonuclear cells, the inhibition of leucocyte and macrophage migration and aggregation, and the regulation of fibroblast proliferation [65]. HA is an endogenous stimulator of interleukin‐1 (IL‐1) production, and IL‐1 affects fibroblasts proliferation and collagenase production [30]. Therefore, according to Hiro et al., HA is an endogenous IL‐1 inducer and may play important roles in the pathological and/or physiological changes of connective tissues [30]. It is known that HA is highly non‐antigenic and non‐immunogenic, because it has high structural homology across species and weak interactions with blood components [66]. HA’s degradation products are thought to contribute in scar formation because the increased amounts of HA fragments from the action of hyaluronidase in HA induce increased scar formation. There are various commercial preparations of HA in different forms, such as films, microspheres, liposomes, fibres and hydrogels, which have been used for more than 20 years worldwide [63]. Although the above‐mentioned commercial preparations of HA have mainly been used in animal studies, it also provides useful information regarding the effect of hyaluronate in the prevention of postoperative peridural scar adhesion after laminectomy in spine surgery; however, additional clinical trials regarding the use of HA‐based gels should be performed to confirm its effects in human subjects [67, 68]. Use of the hyaluronic acid‐carboxymethylcellulose membrane Seprafilm as a solid anti‐adhesion barrier agent is one of the therapeutic approaches used to reduce postoperative scar formation and is effective in promoting peripheral nerve regeneration at the repair site [69]. In addition, HA‐carboxymethylcellulose solutions improve nerve regeneration and reduce perineural scar formation and adhesion after sciatic nerve repair [70]. It has been confirmed that direct application of HA‐carboxymethylcellulose in transected nerves may limit axonal outgrowth by contact with regenerating axons; therefore, HA‐carboxymethylcellulose barriers may prove to be a tool to prevent neuroma formation through inhibiting axonal growth [71]. On the contrary, according to some other studies, the role of HA solution in axonal outgrowth is dose‐dependent, because high dose of HA (100–1000 μg/ml) topically used is characterised by significantly increased axonal outgrowth compared with HA solution (10 μg/ml) applied in the control group, in which axonal outgrowth did not occur [72]. Some authors describe the early effect on nerve regeneration of continuous local delivery of nerve growth factor (NGF) and the local incorporation of HA inside a newly manufactured nerve conduit material from fresh human amniotic membrane [73]. Additionally, other authors have demonstrated that the combination of vascular endothelial growth factor (VEGF) gene therapy and a HA film sheath‐enriched microenvironment may synergistically promote peripheral nerve regeneration [74]. The microenvironment of neuron cells plays a crucial role in regulating neural development and regeneration [75].
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HA and its derivatives may also promote regeneration of injured nerves through realignment of the fibrin matrix, and they can provide a suitable environment for axonal ingrowths [25]. In another animal experimental study, a single topical dose of HA enhanced the nerve regeneration process in hindlimb rat and rabbit models by preventing perineural scar formation after peripheral nerve repair [31, 76]. New data in the literature have shown that HA‐based biomaterials have been applied in a wide range of medical and biological fields and play important roles in neural regeneration [75].
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3. Tacrolimus
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Tacrolimus, also known as FK506 or Fujimicin (C44H69O12), is a macrolide immunosuppressive drug that is approved for the prevention of allograft rejection [25], but it is well known that tacrolimus can also increase nerve regeneration and facilitate allografting of nerves via immunosuppression [18]. Chemically, tacrolimus is a 23‐membered macrolide lactone. It is a powerful and selective anti‐T‐lymphocyte agent that was discovered in 1984 and later approved by the U.S. Food and Drug Administration (FDA). This agent, isolated from the fungus Streptomyces tsukubaensis, has a mechanism of action similar to that of cyclosporin A. The first preliminary report on FK506 was presented in 1986 at the 11th International Congress of the Transplantation Society [77], and the first experimental reports were published in 1987 [78–80]. These early reports demonstrated that FK506 is a potent immunosuppressant that acts in vitro via inhibiting interleukin 2 (IL‐2) production, as well as by inhibiting the response of mixed lymphocyte cultures at concentrations 32–100 times lower than that of cyclosporin A [81]. It means that despite similar mechanisms of action, tacrolimus is 50–100 times more potent than cyclosporin A [82].
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Tacrolimus is able to modulate the immune system, inhibit T‐cell function by binding to FK binding proteins (FKBP) and mediate immunosuppression by inhibiting calcineurin and calcium and calmodulin‐dependent phosphatase. The primary biological effect of calcineurin inhibition includes the decrease of the production of inflammatory cytokines such as tumour necrosis factor (TNF)‐α, interleukin‐2 and interferon‐γ [28]. The drug’s immunosuppressive effects are mediated largely through FKBP12, which is involved in intracellular calcium flux and cycle regulation [83]. Tacrolimus realises its effect by binding to its receptors (FKBP12 and FKBP52). The FKBP12 receptors are responsible for immunosuppressive effects, whereas the FKBP52 receptors are related to neuroregenerative effects. These effects of tacrolimus have been shown experimentally in multiple models of nerve injury during the past decade when tacrolimus was used in sub‐immunosuppressive doses, and these findings have stimulated interest in characterising its neurophysiologic effects on nerve regeneration [84]. Tacrolimus sustains nerve regeneration with both systemic and local administration [85]. In vitro and in vivo experimental models have proven that tacrolimus increases neurite elongation and accelerates the rate of peripheral nerve regeneration [29]. In addition, there is evidence from in vivo experimental studies that highlight that tacrolimus has a neuroprotective role in the central nervous system through its direct impact on its various cell populations [86]. Recently, some studies have demonstrated the effect of tacrolimus in spinal surgery where it was found that topical application of tacrolimus could inhibit fibroblast proliferation and prevent epidural scar adhesion after laminectomy in a rat model [87], and it is worth mentioning that tacrolimus has been successfully used topically in spinal cord trauma for neuroprotection and local regeneration [88].
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Tacrolimus is an essential drug for the conventional immunosuppression regimen for solid organ transplantation. The use of tacrolimus in post‐transplant immunosuppressive regimens can enhance nerve regeneration and the growth of axon sprouts into donor tissue [89]. It has been demonstrated that tacrolimus has a powerful effect on promoting axon regeneration through its immunosuppressive and neurotrophic action [90]. This (neurotrophic) action can be completely prevented in vitro by the addition of a monoclonal antibody against FKBP52 [84].
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The topical effects of tacrolimus on peripheral nerve have not been well investigated to date and the exact mechanism by which tacrolimus affects nerve regeneration is unclear, but outcomes data, so far, have been promising [89]. Additionally, the results of the use of tacrolimus in peripheral nerve regeneration differ in the literature. The relative variability of the results of experimental studies of nerve injures can be explain by the variety of models and testing methods used [91]. Prior studies have shown that FK506‐FKBP12 interaction may lead to a neuroregenerative effect through increased neuronal expression of a growth cone‐associated protein GAP‐43, but there is evidence that this occurs through inactivation of neuronal nitric synthetase [92, 93]. Moreover, axon regeneration from tacrolimus is realised predominantly through its binding to FKBP‐12, which activates GAP‐43 and the transforming growth factor (TGFb1) pathway [26]. Tacrolimus can promote peripheral nerve regeneration through reducing scar formation; however, little is known about how tacrolimus reduces scar formation [94, 95]. Que et al. suggest that tacrolimus‐induced fibroblast apoptosis contributes to the suppression of fibroblast proliferation and then causes the reduction of scar formation in the damaged nerve; in fibroblasts, apoptosis of tacrolimus involves c‐Jun N‐terminal kinase (JNK) and extracellular‐signal‐regulated kinase [94].
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Some studies have shown a positive effect of tacrolimus after it was used in different allograft and isographs. Earlier axon regeneration in allografts with FK506 compared to allografts without FK506 was demonstrated experimentally [96]. Systemic application of tacrolimus at doses of 0.6 mg/kg found the amount of myelin debris in autologous nerve grafts to be decreasing [97]. This can be explained by the reduction of macrophage infiltration after tacrolimus administration. The reduction of scar formation at the site of nerve repair by the above‐mentioned mechanisms has been associated with better morphologic and nerve function recovery. Recently, we published two original articles that compare the effects of HA and FK‐506 on nerve regeneration. We found that our electrophysiological and biomechanical measurements as well as our results of functional evaluations indirectly indicate that the effects of HA and FK506 on nerve regeneration are similar [98, 99].
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4. Cyclosporin A
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Cyclosporin A is a neutral lipophilic cyclic undecapeptide that was isolated in 1971 from the fungus Tolypocladium inflatum and came into medical use in 1983 [100]. Its immunosuppressive function was first reported in 1972 by Sandoz Laboratories [101]. Discovery of cyclosporine A has revolutionised transplantation medicine, which requires the application of immunosuppressive therapy. Cyclosporin has been widely applied as an immunosuppressive substance in organ transplantation in association with other drugs, both in vital and non‐vital organs, such as skin, nerve and muscles. It is known that cyclosporin A has similar immune‐suppressing characteristics to tacrolimus, but tacrolimus has a more potent effect with equal volumes of drug [95]. There are data in the literature that cyclosporin A was used experimentally in order to investigate its anti‐scarring effects on peripheral nerves both ultrastructurally and in gross post‐surgical and histopathological analyses [102]. Cyclosporin’s mechanism of action in nerve regeneration remains controversial [103]. However, probable mechanisms include inhibiting white blood cell proliferation and/or differentiation and inhibiting Ca2+‐dependent cell injury [104]. Besides the above‐mentioned mechanism, cyclosporin A acts with other anti‐inflammatory effects in preventing scar formation because it can block the transcription of cytokine genes in activated T cells, whereas on the another hand, it is well established that cyclosporin A inhibits the phosphatase activity of calcineurin through the formation of a complex with cyclophilin, which regulates nuclear translocation and subsequent activation of nuclear factor of activated T cells (NFAT) transcription factors [105]. Calcineurin plays an important role in the T‐cell receptor‐mediated signal transduction pathway and is identified as the common target for cyclosporin A and tacrolimus [106].
\n
The role of cyclosporin A in peripheral nerve regeneration after peripheral nerve allografting has been investigated in experimental models immunosuppressed with cyclosporine for more than two decades [107]. It is worth mentioning that most of these studies were concentrated on allograft survival, rather than on the direct effect of cyclosporin A on peripheral nerve regeneration [103]. Some authors have investigated the efficacy of cyclosporine A in large‐ and small‐diameter nerve grafts as well as in long and short allografts. They have found better nerve regeneration in large‐diameter nerve grafts than in small‐diameter nerve grafts, whereas with regard to the length of the grafted nerve, short nerve allografts give higher axon counts than long ones, the same as with autografts [108]. Recently published data suggest that even though cyclosporin A is effective at reducing graft rejection, axon regeneration is still superior in autografts versus immunosuppressed allografts [109]. Furthermore, cyclosporin A effectively prevented postoperative epineurial fibrosis on rat sciatic nerves after peripheral nerve surgery with no adverse effects after topical application [102]. The application of cyclosporin A in a silicon conduit neurorrhaphy resulted in improvement of functional recovery and quantitative morphometric indices of sciatic nerves in diabetic rats [110].
\n
\n
5. Melatonin
\n
Melatonin, which is also known as N‐acetyl‐5‐methoxytryptamine, is a hormone and was first identified in bovine pineal extracts [35]. Melatonin is the main hormone of the pineal gland and is an important signalling molecule that occurs in many organisms as well as in plants and fungi [33]. The pineal gland is in the middle of the brain and secretes melatonin, a hormone that regulates when you sleep at night and wake up in the morning, as well as other numerous aspects of circadian biology [111]. Melatonin has an effect on the morphologic features of the nerve tissue, suggesting its neuroprotective, free‐radical scavenging and antioxidative and analgesic effects in degenerative diseases of peripheral nerves [25]. There are different opinions among authors regarding the protective effect of melatonin in stimulation of peripheral regeneration, because some authors have reported toxic effects of melatonin on peripheral nerves [33]. However, nowadays there is enough evidence from the literature showing that melatonin has a useful effect on axon length and sprouting after traumatic events to peripheral nerves [34]. The beneficial effects of melatonin administration on the recovery of injured nerves may be attributed to its antioxidant properties [112]. Melatonin has an effect on superoxide dismutase, which is an important antioxidative enzyme that is involved in redox regulation of regulative stress, and would exert melatonin’s beneficial effects by preserving the superoxide dismutase reactivity following peripheral nerve injury [113]. The rhythm of melatonin defines the activity of glutathione peroxidase and consequently also glutathione reductase. It is thought that the involvement of melatonin in the control of redox processes depends on its high‐affinity binding to cytosolic quinone reductase 2, previously believed to be a melatonin receptor [114]. Through a variety of experimental neuropathologies involving nitric oxide (NO), it was confirmed that melatonin exerts its neuroprotective role after peripheral axotomy via reduction of oxidative damage [115]. The neuronal isoform of nitric oxide synthetase (nNOS), an NADPH‐dependent diaphorase, is considered to play a role in motoneuron death induced by nerve transection. In addition, it is known that exogenous melatonin can prevent neuropathy development via the inhibition of lipid peroxidation in renal tissue and the inhibition of TGF‐β, which limits the effects against fibrosis [116]. Furthermore, data show that melatonin can significantly promote Schwann cell proliferation and can improve nerve regeneration after peripheral nerve injury via this mechanism both in vitro and in vivo. The functional recovery of damaged nerves was estimated by the amount of Schwann cells and the number of re‐innervated muscle motor end‐plate targets [117]. Furthermore, it is worth mentioning that Turgut et al. have experimentally demonstrated in rats that melatonin prevents neuroma formation after transacting the sciatic nerve by enhancing axonal regeneration [118]. Recently, some studies have shown the positive effect of melatonin on preventing scar formation, increasing nerve regeneration and improving functional recovery [119, 120]. However, the exact mechanisms by which melatonin limits fibrosis are currently unclear.
\n
\n
6. Methylprednisolone
\n
Methylprednisolone is an anti‐inflammatory pharmacological agent that has found widespread use in treatment of many pathological disorders in humans. It has also been experimentally investigated intensely for preventing scar formation and nerve regeneration because it is considered to have a neuroprotective role. Generally, glucocorticoids are anti‐inflammatory substances that are often used to alleviate tissue oedema and trauma‐induced inflammatory response because they can down regulate the expression of pro‐inflammatory factors, such as tumour necrosis factor‐α and interleukin‐1β [121]. These pro‐inflammatory factors can increase the expression of induced nitric oxide synthase in the injured region, leading to nitric oxide production and cell apoptosis [122]. There are some mechanisms by which glucocorticoids can express their anti‐inflammatory effects in central and peripheral nerve system. However, one possible mechanism by which methylprednisolone inhibits nerve inflammation is its inhibition of CD3‐positive inflammatory cell infiltration of local tissue [123]. It was found that higher doses of methylprednisolone have a neuroprotective role in injured nerves through inhibition of oxygen‐free radical‐induced lipid peroxidation [124]. Therefore, through inhibition of lipid peroxidation, methylprednisolone can retard both anterograde and retrograde nerve degeneration after peripheral nerve injury. Moreover, the steroid expresses its anti‐inflammatory effects via inhibition on responsive cells and consequently recruitment of macrophages [125]. Regarding these anti‐inflammatory effects, inhibition of phospholipase A2 activity should be mentioned, along with prevention of granulocyte, mast cell and macrophage degranulation, inhibition of macrophage migration‐inhibitory factor and stabilisation of the lysosomal membrane, which are beneficial for treating injured nerves [39]. In the same study, the effect of preoperative locally administered dexamethasone on the recovery of crushed nerves was examined, and the authors concluded that local dexamethasone is more effective than systemic dexamethasone [39]. Systemic application in rats of moderate doses of methylprednisolone, i.e. 15–30 mg/kg, can effectively increase peripheral nerve regeneration, and it was also found that local administration of the drug can have the same positive effects as those of systemic administration while reducing systemic side effects [126]. Moreover, it was found that dexamethasone loaded in silicone tubes can improve functional recovery and morphometric indices of the sciatic nerve, and it was confirmed that topical administration of dexamethasone on peripheral nerve offers the benefits of cost savings as well as avoiding the complications associated with systemic administration [38]. The effect of methylprednisolone in suppressing scar formation and improving axonal regeneration after transection and suture of rat peripheral nerves was described many years before in rats [36].
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Recent experimental studies have demonstrated that topical application of methylprednisolone can be realised using various methods, for example, in various materials such as silicon tubes [38], amniotic membranes [125] and microsphere sustained‐release membranes [126], in order to avoid the rapid destruction of methylprednisolone at the site of nerve repair.
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7. Vitamin B12
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Vitamin B12, also called cobalamin, is a water‐soluble vitamin with multiple functions in organisms, although in comparison with other nutrients, the body needs them in relatively small amounts. It is naturally present in animal products, fish, meat, poultry, eggs, milk and milk products [127]. There are several forms of vitamin B12, which contains mineral cobalt, so for this reason, compounds with vitamin B12 activity are collectively called cobalamins and the active forms are methylcobalamin and 5 deoxyadenosylcobalaminin [128]. Vitamin B12 as a coenzyme induces conversion of homocysteine to methionine in order to facilitate synthesis of nucleic acids and proteins. Therefore, it accomplishes the following essential nerve function, such as promotion of nerve regeneration owing to axoplasm flow within the neuraxon, in order to normalise the neuraxon’s skeleton protein transportation as well as accelerate the formation of the myelin sheath [129]. Vitamin B12 in combination of B1 (thiamine) and B6 (pyridoxine) reduced degenerating processes in the nervous system, and therefore, this combination has been clinically administered [130]. Furthermore, this vitamin is involved in the metabolism of every cell in the human body, especially affecting DNA synthesis and fatty acid and amino acid metabolism [131]. It is known that B12 deficiency leads to deficiency in methionine, which is required for the synthesis of both phospholipids and myelin; therefore, it is an essential element in the maintenance of nerve functions because it induces synthesis of the myelin sheath and improves nerve conduction velocity. In addition, it was found that vitamin B12 increased the number of Schwann cells and myelinated nerve fibres, and the diameter of axons, through which effects it can promote the regeneration of myelinated nerve fibres and the proliferation of Schwann cells [132]. In addition, vitamin B12 has shown antioxidant properties because it is also a good scavenger of reactive oxygen species and is suggested to be a good neuroprotectant. Moreover, vitamin B complex or vitamin B12 can increase the expression of brain‐derived neurotrophic factor (BDNF) in injured nerves at both mRNA and protein levels, therefore promoting the regeneration and functional recovery of injured nerves through increasing BDNF expression [41]. Some authors have shown that vitamin B12 provides a basis for more beneficial treatments of nervous disorders through both systemic and local delivery of high doses of methylcobalamin to target organs, which has been shown to have the potential to treat peripheral nerve injury [40]. Inasmuch as the amount of vitamin B complex and vitamin B12 vary in cases of crush nerve injuries, it is necessary to administrate these vitamins in the acute phase of nerve injury in order to enhance nerve regeneration [42].
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8. Riluzole
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Riluzole (2‐amino‐6‐trifluoromethoxy‐benzothiazol) is a benzothiazole anti‐convulsant and the only U.S. Food and Drug Administration (FDA)‐approved drug to treat amyotrophic lateral sclerosis (ALS) [133]. Riluzole is a sodium/glutamate antagonist that has been shown to have a neuroprotective effect, recently entered clinical testing for spinal cord injury [134] and currently is under Phase III clinical trial for the treatment of spinal cord injury (ClinicalTrials.gov: NCT01597518) [135]. Its neuroprotective effects are a result of the blockade of sodium channels and, consequently, prevention of Ca2+ overflow [136]. In experimental trials in animal models, it was successfully used to reduce symptoms in neurodegenerative disease and neural tissue injury, and these effects can be explained by its inhibition of presynaptic glutamate release through blocking voltage‐gated sodium channels [133]. It is known that in vitro application of riluzole to adult dorsal root ganglion neurons gives a neuroprotective effect via promotion of neurite outgrowth in terms of number, length and branch [137]. For nerve regeneration after nerve injury, neurite outgrowth of surviving neurons is very important in order to reinervate target tissue. In addition, riluzole inhibits neuro‐excitotoxicity in animal models of neural injury, and soon after its administration, it can sufficiently reduce pain from nerve root compression and can prevent development of neuronal dysfunction in the nerve root and the spinal cord [138]. Recently, riluzole was clinically approved for the treatment of motor neuron disease, and experimental research is now underway for the assessment of its role on nerve regeneration processes after peripheral nerve injury [46].
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\n
9. 4‐Aminopyridine
\n
4‐Aminopyridine (4‐AP) is a potassium channel blocker with the chemical formula C5H4N─NH2 that it used as a research tool in order to classify the subtypes of the potassium channel [139]. It has shown clinical efficacy in the treatment of neurological disorders such as multiple sclerosis [140]. The mechanisms of action of 4‐AP can explain by its effect in allowing impulse conduction in demyelinated axons by blocking K+ channels that allow leakage of K+ from these axons and thereby enabling axons to restore the level of depolarisation required for propagation of action potentials [141]. Recently, there are data from literature that 4‐aminopyridine is a potent small molecule with neuroregenerative properties that enhances both the speed and extent of functional recovery after acute peripheral nerve injury, because it promotes remyelination [142]. The same authors have found that 4‐aminopyridine treatment enables differentiation between incomplete and complete lesions more rapidly compared with existing approaches [142].
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\n
10. Verapamil
\n
Verapamil belongs to the class of medications called calcium channel blockers. Besides its effects in the cardiovascular system, recently some experimental studies have investigated the role of verapamil in the peripheral nervous system, and it has been shown to reduce scar formation through inhibiting fibroblast adhesion and proliferation in vitro [143]. However, it is not clear whether topical application of verapamil after surgical nerve repair in vivo could prevent scar formation and promote nerve regeneration [44]. Apparently, this role of verapamil consists of stimulation of the endogenous anti‐inflammatory reaction and decreasing pro‐inflammatory processes by a channel blocker, therefore causing pain modulation or nerve regeneration [43]. The effect of calcium channel blockers in the reduction of scar formation was first reported by Lee and Ping [144]. There are two mechanisms by which verapamil can prevent scar formation: by reducing the biological activity of cells through inhibiting signal transduction inside and outside fibroblasts, and by suppressing the synthesis and secretion of collagen and extracellular matrix through changing fibroblast morphology [44].
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The overall effects and mechanisms of the above‐mentioned pharmacological agents in the prevention of scar formation and improved nerve regeneration are presented in Table 1.
\n
Pharmacological agents
Effects
Mechanisms of action
References
Hyaluronic acid
Reduce the extent of scar formation and nerve adhesions
Via proliferation and chemotaxis of granulocyte phagocytosis and degranulation, and macrophage motility
Neuroprotective role via reduction of scar formation
Through encouraging fibroblast apoptosis, it contributes to the suppression of fibroblast proliferation. Fibroblast apoptosis by tacrolimus involves c‐Jun N‐terminal kinase (JNK) and extracellular‐signal‐regulated kinase
FK506‐FKBP12 interaction may lead to a neuroregenerative effect through increased neuronal expression of growth cone‐associated protein GAP‐43 that probably occurs through inactivation of neuronal nitric synthetase
It is well established that cyclosporin A inhibits the phosphatase activity of calcineurin through the formation of a complex with cyclophilin, which regulates nuclear translocation and subsequent activation of nuclear factor of activated T cells (NFAT) transcription factors
Via reduction of oxidative damage, melatonin exerts its neuroprotective role after peripheral axotomy in a variety of experimental neuropathologies that involve nitric oxide (NO)
Owing to axoplasm flow within the neuraxon, in order to normalise the neuraxon’s skeleton protein transportation as well as accelerating the formation of the myelin sheath
Through its effect in allowing impulse conduction in demyelinated axons by blocking K+ channels that allow leakage of K+ from these axons and thereby enabling axons to restore the level of depolarisation required for propagation of action potentials
Reduce scar formation and promote nerve regeneration
There are two mechanisms by which verapamil can prevent scar formation: by reducing the biological activity of cells through inhibiting signal transduction inside and outside fibroblasts, and by suppressing the synthesis and secretion of collagen and extracellular matrix through changing fibroblast morphology
The effects and mechanisms of pharmacological agents in nerve regeneration.
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\n
11. Discussion
\n
There have been many efforts to diminish scar formation and perineural adhesion as well as to improve nerve regeneration after microsurgical nerve repair. Various surgical techniques and several different pharmacological agents have been used for this purpose. The evaluation of the effects of these pharmacological agents in the prevention of scar formation and nerve regeneration in experimental animals is performed by electrophysiological measurements and through assessing functional recovery, whereas after sacrificing the animals, other methods have been used, such as macroscopic, histomorphometric, immunohistochemical and biomechanical techniques [70, 91, 98, 99]. Ozgenel found that nerves treated with HA have a significant reduction in perineural thickness compared to nerves treated with just saline (P < 0.05). Besides that, this author found better mean conduction velocities (MCVs) and faster functional recovery in HA‐treated nerves (0.82 ± 0.08 m/s) compared with nerves treated with saline, in which the MCV was 0.76 ± 0.04 m/s (P < 0.05) [31]. Park et al. found that topical application of HA carboxymethylcellulose solutions in rats significantly reduced nerve adherence score and the number of cellular components compared with the saline group (control group) (P < 0.05) [70]. The authors concluded that HA carboxymethylcellulose solutions improved nerve regeneration and reduced perineural scar formation and adhesion after sciatic nerve repair [70]. Furthermore, the same results were demonstrated by Adanali et al. in rabbit sciatic nerves where they used HA carboxymethylcellulose membranes in the experimental group and saline in the control group; they observed that adhesion in the surrounding tissues was significantly less in the HA carboxymethylcellulose membranes group than in the saline group [69]. Ikeda et al. found that local application of HA in the sciatic nerve was the most effective at reducing extraneural and intraneural connective tissue, compared with the steroid and saline groups [145]. By electrophysiological measurements, Ikeda et al. also found that the latencies of the HA and steroid groups were much shorter than that of the neurolysis group (2.14 ± 0.20, 1.92 ± 0.11 and 1.91 ± 0.15 m/s, respectively), but longer than that of the control group (1.68 ± 0.07 m/s). Similar results were found by histological examination, because scar tissue in the neurolysis group was thicker and more voluminous than that in the HA group or the steroid group [145]. In addition, Zor et al. found significantly less scar formation (P < 0.01) and significantly higher peak amplitudes in rats (P < 0.01) that received a combination treatment of vascular endothelial growth factor gene therapy with HA [74].
\n
Shahraki et al. demonstrated earlier axon regeneration in allografts with FK506 compared to allografts without FK506 (P < 0.05) [96]. Yan et al. found that short treatment courses of 10 and 20 days with FK506 (in the graft model) were sufficient to reduce functional recovery time by 15 and 21%, respectively, compared with negative controls assessed by walking track analysis [90]. In addition, via a functional study, Azizi et al. confirmed faster recovery of the regenerated axons in the inside‐out vein graft/FK506 group than that for the inside‐out vein graft without FK506 (control group) (P < 0.05). The same statistically significantly difference was found when comparing these groups regarding the mean gastrocnemius muscle weight ratio (P < 0.05) [91]. Que et al. showed that scar area had a significant positive correlation with the fibroblast number, as detected by linear correlation analysis [94]. Other authors reported that tacrolimus can increase the number of axons and their myelinated axons by 40% and reduce by half the time to neurological recovery [29]. Furthermore, Li et al. found that after application of FK506 loaded in a chitosan guide, the amplitude and velocity of compound muscle action potential (CMAP) reached 60 and 73% of the control values, respectively [146].
\n
In order to compare the effects of HA and FK506 on peripheral nerve regeneration in rabbits after the drugs were topically applied at the site of sciatic nerve, we used electrophysiological, macroscopic and microscopic methods, while functional assessment was performed via toe‐spreading reflex. According to our results, HA and FK506 appear to have similar effects (P > 0.05) with respect to preventing scar formation and improving nerve regeneration compared with saline (P < 0.05) [80, 98]. However, it should be mentioned that we observed no significant differences in biomechanical properties in the HA and FK506 groups compared to the saline group (P > 0.05) [99].
\n
Çetinalp et al. demonstrated that animals treated with cyclosporin A had statistically significant lower perineural adhesion and better separability than the saline group (control group) (P < 0.0001) [102]. However, these authors did not find a significant difference in the wound‐healing characteristics or neurological functions between the treatment (cyclosporin A) group and the control group (P > 0.05) [102]. In an experimental rat sciatic nerve injection injury model established by penicillin G potassium injection, Erkutlu et al. randomly divided rats into three groups based on the length of time after nerve injury induced by cyclosporin A administration (30 minutes, 8 or 24 hours), recorded electrophysiological measurements (compound muscle action potentials, pre‐injury, early post‐injury [within 1 hour]and 4 weeks after injury) and then compared the results of the experimental groups with the control group. Finally, they found significant improvement of the compound muscle action potential amplitude value only when cyclosporin A was administered within 30 minutes of the injection injury (P < 0.05) [104].
\n
Turgut et al. examined the gross morphology of neuroma formation in the proximal nerve segment via macroscopic and microscopic findings, and the surgical pinealectomy group without application of melatonin caused a proliferation of connective tissue and large neuroma formation at the proximal ends of transacted nerves compared with the surgical pinealectomy group and the group given melatonin (P < 0.005) [118]. In addition, Kaya et al. demonstrated a beneficial effect on axonal regeneration and functional recovery in the experimental group in which melatonin was applied after stripping of the epineurial vessels compared with other groups without melatonin application [119].
\n
Recently, Sadraie et al. found that at 8 weeks after surgery, sciatic functional index, withdrawal reflex latency test, electrophysiological values and histological results in the amniotic membrane with the betamethasone group were improved compared to those in the control and sham groups (P < 0.05) [125]. Furthermore, Feng and Yuan found better and faster functional recovery in the dexamethasone‐administered group compared to other groups without dexamethasone (P < 0.05); therefore, they concluded that dexamethasone can promote functional recovery after sciatic nerve crush injury [123]. In addition, Sun et al. via morphological (by electron microscopy) and functional analysis observed that treatment with dexamethasone or vitamin B12 alone, or treatment with both agents, led to a much larger number of Schwann cells and myelinated nerve fibres compared with that in the saline group (P < 0.05) [41]. Okada et al. showed in a rat sciatic nerve injury model that continuous administration of high doses of methylcobalamin can improve nerve regeneration and functional recovery [40].
\n
According to Shortland et al., a single dose of 0.1 µM riluzole was sufficient to promote neuronal survival in neonatal dorsal root ganglion cultures, whereas repeated riluzole administration was necessary in adult cultures. For both types of injuries, riluzole enhanced neurite outgrowth (number, length and branch pattern) significantly more on the injured side in comparison with the contralateral side [137].
\n
Tseng et al. found that once‐daily administration of 10 μg of 4‐aminopyridine enhanced the speed of recovery from crush injury when it was used as early as 3 days post‐injury in mice treated daily (beginning 24 hours post‐injury), and a significant improvement (>25%) in gait function was confirmed over the control groups (vehicle‐treated animals). Furthermore, at 5 and 8 days post‐injury, 4‐AP‐treated mice showed statistically significant twofold greater levels of improvement than the control groups [142].
\n
Han et al. carried out a study in which the right sciatic nerve of adult rats was transected and sutured, and then a gelfoam soaked with verapamil solution for 4 weeks was topically applied by them. The results showed that verapamil can inhibit the secretion of extracellular matrix from fibroblasts in vivo through suppression of type I and III collagen secretion. Verapamil also increased the total number of axons as well as the number of myelinated axons more than in the control group, in which gelfoam soaked with physiological saline was topically applied (P < 0.05) [44].
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\n
12. Conclusions
\n
Generally, it should be mentioned that the most of the experimental research discussed in this chapter was conducted in rats and rabbits, in which the above‐mentioned pharmacological agents have been applied (mainly locally in sciatic nerve). The success of the regenerative process of nerve repair in experimental research can be evaluated using a variety of methods, such as morphological, immunohistochemical, electrophysiological, biomechanical and functional evaluation. Some of the pharmacological agents described in this chapter are still only used for experimental purposes, whereas some of them are in clinical use for the treatment of various diseases, and now their neuroregenerative effects will also be explored in experimental animals. However, the success of nerve regeneration depends on the type and degree of nerve injury, age, repair time, operative techniques and the type of materials used. By combining appropriate dosages of these pharmacological agents with improved microsurgical techniques for nerve repair, better experimental results may be achieved in the future, encouraging clinical application of these agents. However, it is understandable that complete regeneration and functional recovery will almost never be achieved, regardless of the operative technique used or the type of pharmacological agent applied.
\n
\n',keywords:"nerve injury, nerve regeneration, pharmacological agents, scar formation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/55017.pdf",chapterXML:"https://mts.intechopen.com/source/xml/55017.xml",downloadPdfUrl:"/chapter/pdf-download/55017",previewPdfUrl:"/chapter/pdf-preview/55017",totalDownloads:1901,totalViews:832,totalCrossrefCites:2,totalDimensionsCites:3,totalAltmetricsMentions:0,impactScore:2,impactScorePercentile:79,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"October 27th 2016",dateReviewed:"March 7th 2017",datePrePublished:null,datePublished:"May 31st 2017",dateFinished:"April 26th 2017",readingETA:"0",abstract:"Peripheral nerve injuries are frequent and represent a significant pathology of the peripheral nervous system because, despite operative techniques and successful microsurgical repair, in most cases, the nerve repair is followed by scar formation. Numerous investigations have been carried out with the aim of finding pharmacological substances that can prevent scar formation and speed up the regeneration of repaired nerves. This chapter is dedicated to the efforts of many researchers to find different pharmacological agents with local effects on the improvement of nerve regeneration. Numerous experiments have been carried out in mice and rabbits using hyaluronic acid, tacrolimus, cyclosporin A, melatonin, vitamin B12, methylprednisolone, riluzole and potassium and calcium channel blockers. In the experimental animal studies, topical pharmacological agents were used at the site of peripheral nerve repair. The effect of these substances is most commonly studied in sciatic nerve injury in experimental animals. Their effects were evaluated using a variety of methods, such as morphological, biomechanical, electrophysiological and functional evaluation, and the above‐mentioned substances, have been shown to have neuroprotective and neuroregenerative properties though different mechanisms.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/55017",risUrl:"/chapter/ris/55017",book:{id:"5852",slug:"peripheral-nerve-regeneration-from-surgery-to-new-therapeutic-approaches-including-biomaterials-and-cell-based-therapies-development"},signatures:"Agon Mekaj and Ymer Mekaj",authors:[{id:"199721",title:"Prof.",name:"Ymer",middleName:null,surname:"Mekaj",fullName:"Ymer Mekaj",slug:"ymer-mekaj",email:"ymer.mekaj@uni-pr.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Pristina",institutionURL:null,country:{name:"Kosovo"}}},{id:"200047",title:"Dr.",name:"Agon",middleName:null,surname:"Mekaj",fullName:"Agon Mekaj",slug:"agon-mekaj",email:"agon.mekaj@uni-pr.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Hyaluronic acid",level:"1"},{id:"sec_3",title:"3. Tacrolimus",level:"1"},{id:"sec_4",title:"4. Cyclosporin A",level:"1"},{id:"sec_5",title:"5. Melatonin",level:"1"},{id:"sec_6",title:"6. Methylprednisolone",level:"1"},{id:"sec_7",title:"7. Vitamin B12",level:"1"},{id:"sec_8",title:"8. Riluzole",level:"1"},{id:"sec_9",title:"9. 4‐Aminopyridine",level:"1"},{id:"sec_10",title:"10. Verapamil",level:"1"},{id:"sec_11",title:"11. Discussion",level:"1"},{id:"sec_12",title:"12. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'McCance KL, Heuther SE. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 5th ed. Philadelphia, USA: Elsevier Mosby; 2006. p 411.'},{id:"B2",body:'Geuna S, Tos P, Titolo P, Ciclamini D, Beningo T, Battiston B. Update on nerve repair by biological tubulization. Journal of Brachial Plexus and Peripheral Nerve Injury. 2014;9:3. 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DOI: 10.1089/neu.2012.2622.'},{id:"B135",body:'Satkunendrarajah K, Nassiri F, Karadimas SK, Lip A, Yao G, Fehlings MG. Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisection. Experimental Neurology. 2016;276:59‐71. DOI: 10.1016/j.expneurol.2015.09.011'},{id:"B136",body:'Fehlings MG, Wilson JR, Karadimas SK, Arnold PM, Kopjar B. Clinical evaluation of a neuroprotective drug in patients with cervical spondylotic myelopathy undergoing surgical treatment: Design and rationale for the CSM‐protect trial. Spine (Philadelphia Pa 1976). 2013;38:S68‐S75. DOI: 10.1097/BRS.0b013e3182a7e9b0.'},{id:"B137",body:'Shortland PJ, Leinster VH, White W, Robson LG. Riluzole promotes cell survival and neurite outgrowth in rat sensory neurones in vitro. European Journal of Neuroscience. 2006;24:3343‐3353. DOI: 10.1111/j.1460‐9568.2006.05218.x'},{id:"B138",body:'Nicholson KJ, Zhang S, Gilliland TM, Winkelstein BA. 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Immunophilin FK506 loaded in chitosan guide promotes peripheralnerve regeneration. Biotechnology Letters. 2010;32:1333‐1337. DOI: 10.1007/s10529‐010‐0287‐8'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Agon Mekaj",address:null,affiliation:'
Clinic of Neurosurgery, Faculty of Medicine, University of Prishtina, Prishtina, Kosovo
Institute of Pathophysiology, Faculty of Medicine, University of Prishtina, Prishtina, Kosovo
Clinic of Neurosurgery, Faculty of Medicine, University of Prishtina, Prishtina, Kosovo
Institute of Pathophysiology, Faculty of Medicine, University of Prishtina, Prishtina, Kosovo
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1. Introduction
Dietary polyphenols have interesting spectrum biological properties, including radical scavenging activity [1]. Anthocyanins are one of essential classes in the polyphenol family [2]. These are the plant pigments responsible for the bright red-orange to blue-violet colors of many fruits and vegetables [3]. Since these are natural colored compounds, many pieces of literature come with their application as coloring or coloring material, especially in the food industry [4, 5, 6, 7, 8, 9]. Naturally, these compounds found in glycoside form can collectively be called anthocyanins. At the same time, their aglycon forms are commonly called anthocyanidins [10]. The common aglycon forms are cyanidin, delphinidin, peonidin, petunidin, malvidin, and pelargonidin. The color pigments are most abundant in berries like black currants, elderberries, blueberries, strawberries, etc., red and purple grapes, red wine, sweet cherries, eggplants, black plums, and red cabbage, etc.
The basic structure of anthocyanins is the flavylium cationic ring in which oxygen carries a positive charge. The positively charged species exhibit several equilibrium structures due to different transformations like proton transfer, isomerization, and tautomerization under various pH conditions [11]. All molecules of a group of anthocyanins have their absorption range in the visible spectrum due to effective π conjugation within the molecule. These are the largest group of water-soluble pigments in the plant kingdom. Experimental and theoretical reports show an exponential increase in findings related to its properties, color, co-pigmentation, pH effect, antiradical properties, etc. [12, 13, 14, 15, 16, 17].
The delphinidin (1a) and its four modifications (1b, 1c, 1d & 1e) are selected for the study. The structure of 1a having three rings A, B, and C, where A & C are fused rings and B connected with A-C through a single bond. The structures of compounds under consideration are shown in Figure 1. The colored pigments with other colorless natural products are now proven to be very impressive due to their improved activity in the sense of color and property. Hence to enhance the property, the colorless, most important, small, widely studied polyphenol gallic acid is taken and coupled with 1a through their 3 and 4’ OH bonds and respectively formed delphinidin-3-O-gallate (1c) and delphinidin-4’-O-gallate (1e). Also, the results are compared with its glucose forms delphinidin-3-O-glucoside (1b) and delphinidin-4’-O-glucoside (1d).
Figure 1.
Structures of compound considered for the study.
Gallic acid (3,4,5- Trihydroxy benzoic acid) and its derivatives have been found in various natural sources like nuts, tea, grapes, gallnut, oak bark, etc. Biological studies show that gallic acid has variable effects, including antiviral, antioxidant, and anticancer activities [18, 19, 20]. Due to its potent antioxidant activity against free radicals is used in food, cosmetics, and pharmaceutical industries and as a source material for ink and paints [21]. GA possesses the most robust antiradical property than Trolox, and hence, in many cases, this molecule is widely used as a reference compound for antioxidant studies. Green tea contains the highest concentration of GA-based compounds responsible for the plant’s antioxidant capacity [22, 23].
Once the compound possesses potent antioxidant activity and a specific range of absorbance in the visible spectrum can be effectively used for various purposes, especially in the food industry, they seek less hazardous, highly protective materials for coloring purposes. Hence these are colored compounds, and this work concludes the antiradical property of delphinidin and its derivatives with the help of computational methods.
2. Materials and method
2.1 Materials
The present work has utilized a theoretical approach to study the structure and properties of all compounds under consideration. The molecular forms of 1a and 1b were downloaded from the PubChem database in SDF file format and converted to GJF file format by Open Babel [24]. The structures of 1c, 1d, and 1e were drawn using the Gaussview 5.0.8 graphical user interface [25]. All the computational works have been carried out through Gaussian 09 software package to get the output [26]. The spin density (SD) and electron delocalization (DI) analysis are explained with the help of the software Multiwfn 3.6 [27].
2.2 Computational methodology
The present work was carried out using density functional theory (DFT) because it is based on electron density, and antioxidant activity is mainly influenced by electron density [28, 29, 30, 31, 32]. In DFT calculation, 6–311+ G (d, p) basis set with B3LYP (Becke’s exchange functional in conjunction [33] with Lee-Yang–Parr [34]) correlational functional has been used for geometry optimization, computation of harmonic vibrational frequencies, BDE, IP, PDE, PA and ETE calculations. To obtain antioxidant parameters BDE, IP, PDE, PA, and ETE, the geometry optimization of neutral, radicals, anions, and radical cation structures of all the studied molecules are conducted in the ground state both in the gas phase and aqueous phases. Solvent effects on the calculated systems were investigated with the self-consistent reaction field (SCRF) method via the integral equation formalism polarized continuum model (IEF-PCM).
2.2.1 Frontier molecular orbital (FMO) analysis
Frontier molecular orbital theory is an application of MO theory that explains HOMO/LUMO interactions. HOMO is the highest occupied molecular orbital, and LUMO is the lowest unoccupied molecular orbital. Frontier molecular orbital analysis is fundamental because HOMO or LUMO energies and bandgap energies are the key factors that drive the antiradical property of molecules. Since HOMO is in the highest energy state, so easier to remove an electron from this orbital. So in a chemical reaction or bond formation, HOMO is donating electrons, or it acts as a Lewis base or undergoes oxidation. LUMO is the lower-lying orbital; it is empty, so it is easier for LUMO to accept electrons into its orbital or acts as a Lewis acid or undergoes reduction. Reactivity becomes lower when the molecule has a higher bandgap. The distribution of HOMO orbitals and energies is calculated using the DFT-B3LYP/6–311 + G (d, p) level of theory from the optimized structures of 1a and its derivatives.
2.2.2 Radical scavenging activity
Several mechanisms have theoretically explained the radical scavenging mechanism of phenolic compounds. The widely used mechanisms are hydrogen atom transfer (HAT) mechanism (Eq. (1)), single-electron transfer followed by proton transfer (SET-PT) mechanism (Eqs. (2)–(4)), and sequential proton loss electron transfer (SPLET) mechanism (Eqs. (5) and (6)) [35, 36, 37, 38, 39, 40]. These mechanisms have been briefly addressed here.
HAT (hydrogen atom transfer) mechanism
ArOH+X•→ArO•+XHE1
By transferring the hydrogen atom of the –OH group to the radical species, the antioxidant (ArOH) scavenges the free radical (X•) and transforms it into phenoxide radical. The descriptor associated with the HAT mechanism is bond dissociation enthalpy (BDE), and the lower value indicates good radical scavenging activity. The ArO∙ radical species’ stabilizing features, like the resonance delocalization of the electron within the aromatic ring, are the basis of lowest energy and increased antiradical activity.
SET (single electron transfer) mechanism
ArOH+X•→ArOH•++X−E2
Here, the reactive free radicals are neutralized by transferring electrons to them, resulting in anions. The most reactive hydroxyl group in antioxidant compounds provides these electrons and finally becomes a radical cation. The descriptor associated with this mechanism is AIP (adiabatic ionization potential).
SET-PT (single electron transfer followed by proton transfer) mechanism
ArOH+X·→ArOH•++X−E3
ArOH•+→ArO•+H+E4
The first process involves an electron transfer from the antioxidant (Eq. (2)), and the second step consists of a proton transfer from the radical cation (Eq. (4)) generated in the first step. Proton dissociation enthalpy is the descriptor connected with the second phase (PDE).
SPLET (sequential proton loss electron transfer) mechanism
ArOH→ArO−+H+E5
ArO−+X•+H+→ArO•+XHE6
This is also a two-stage mechanism, with the dissociation of the antioxidant into phenoxide anion and proton as the first step (Eq. (5)). The first-step phenoxide anion then interacts with free radicals at a certain pH (Eq. (6)); the compounds generated are similar to those developed in the HAT mechanism. Proton affinity (PA) is the regulating descriptor for the first stage, and electron transfer enthalpy is the driving descriptor for the second stage (ETE).
The Eqs. (7)–(11) are used for analyzing the type of mechanism involved by the compound
BDE=HArO•+HH•−HArOHE7
AIP=HArOH•++He−−HArOHE8
PDE=HArO•+HH+−HArOH•+E9
PA=HArO−+HH+−HArOHE10
ETE=HArO•+He−−HArO−E11
Thus, in the present study, BDE, IP, PDE, PA, and ETE values were used as the primary molecular descriptors to elucidate the radical scavenging activity of the investigated compounds. The enthalpies of hydrogen radicals in the water and gas phase are calculated by G09 software using the DFT/B3LYP/6–311 + G (d, p) level of theory. The enthalpies of the electron (e−) and proton in the gas phase are taken from the commonly accepted values 0.00236 Hartree for proton and 0.00120 Hartree for electron. In contrast, for water, these corresponding values are calculated with the help of the DFT/B3LYP/6–311 + G(d, p) level of theory. The enthalpies of electron and proton in solvent water were computed using the same level of theory with methodology suggested by Markovic et al. (Eqs. (12) and (13)) [41, 42].
Hgas++Ssol→S−Hsol+E12
egas−+ssol→S−esol−·E13
Where Ssol is the solvent molecule solvated by the same kind of molecule, S−Hsol+ and S−esol−· are the charged particles formed. The solvation enthalpies of proton and electron are calculated using the Eqs. (14) and (15), respectively, and that of H• by optimizing hydrogen atom using the same level of theory. The enthalpy of hydrogen radical taken for gas is −0.49764 Hartree and − 0.497466 Hartree for water. The enthalpies of proton and electron in water, respectively, are −0.37725431 Hartree and 0.093551 Hartree.
ΔHsolH+=HS−Hsol+−HSsol−HHgas+E14
ΔHsole−=HS−esol−·−HSsol−Hegas−E15
3. Results and discussion
3.1 Conformation analysis and geometry optimization
To elucidate the reactivity of the compounds towards free radicals, the conformational and geometrical features of compounds are very significant. The structures of 1a and 1b are downloaded from the PubChem database and 1c, 1d, and 1e are constructed from the optimized structure of 1a. The potential energy surface of all five molecules is scanned by using the B3LYP/3-21G level of theory by varying the dihedral angles values in 12 steps of 30° from 0 to 360°. The dihedral angle between aromatic ring B and AC bicyclic in 1a is performed on the dihedral Ф1 (C3, C2, C1ˈ, C2ˈ), and the five OH groups are also scanned as above mentioned procedure. All phenolic OH is in a position that forms hydrogen bonding with the nearest OH. The dihedral Ф1 about (C3, C2, C1ˈ, C2ˈ) of 1a completely reveals the planar geometry of the molecule, whereas other molecules are slightly becoming nonplanar because of the steric cloud around flavylium cationic ring. The dihedral (C3, C2, C1ˈ, C2ˈ) of 1a, 1b, 1c, 1d, and 1e respectively are −179.95499, −158.12940, −167.05569, −169.70713, and 171.29496 degrees.
The lowest energy conformer obtained after the last scan was then subjected to geometry optimization, and B3LYP/6–311 + G(d, p) level of theory with a correlation coefficient of 0.89281 are selected for the study. The crystal structure data of cyanidin are considered for experimental validation of results obtained from the computational analysis since these are not available for delphinidin molecules and tabulated in Table 1 [43]. But the basic structural unit of 1a is similar, except in cyanidin, one OH is missing from the 5′ position. The optimized structures of the five compounds are shown in Figure 2. These optimized structures are considered for further calculations.
Bond
Experimental bond length (AO)
Theoretical
B3LYP 6–31 G (d)
B3LYP 6–31+ G (d, p)
B3LYP 6–311+ G (d, p)
B3LYP 6–311++ G (d, p)
C 2-C1’
1.453
1.44380
1.44380
1.44173
1.44176
C10-C5
1.432
1.43007
1.43002
1.42770
1.42769
C1’-C2’
1.409
1.41731
1.41735
1.41422
1.41423
C6 - C7
1.413
1.41392
1.41390
1.41107
1.41106
C2 –C3
1.396
1.42173
1.42177
1.41918
1.41920
C3’-C4’
1.400
1.40858
1.40863
1.40599
1.40602
C4–C10
1.382
1.40615
1.40614
1.40553
1.40351
C6’-C1’
1.404
1.41542
1.41539
1.41216
1.41218
C9–C10
1.408
1.41223
1.41222
1.40886
1.40888
C7 – C8
1.387
1.39860
1.39860
1.39517
1.39517
Table 1.
Comparison of bond length with experimental values in different basis sets.
Figure 2.
The obtained optimized structures of the compounds using B3LYP /6–311 + G(d, p) level of theory (delphinidin (1a), delphinidin-3-O-glucoside (1b), delphinidin-3-O-gallate (1c), delphinidin-4’-O-glucoside (1d), and delphinidin-4’-O-gallate (1e)).
3.2 Molecular orbital analysis
Frontier molecular orbital analysis gives a detailed account of HOMO/LUMO interactions in the molecule. It is very useful in describing optical and electronic properties as well as the reactivity of a molecule. The HOMO value of the molecule is strongly influenced by radical scavenging activity. The higher the HOMO energy, the easier the electron is being excited and acts substantial donor of the electron. The chemical reactivity of the molecule can be described by knowing the HOMO–LUMO gap. Like that, the distribution of orbitals among the molecule reveals probable sites for the attack of free radicals. The HOMO distribution among molecule 1a is completely distributed on each atom, whereas the LUMO orbitals have distributed all atoms except 3- OH, 3’- OH, and 5’-OH. For the molecules studied here, the distribution of the LUMO distributed among each atom other than 3- OH, 3′- OH, and 5’-OH. So these three bonds are involved in the HOMO-LUMO transition. In 1c and 1e, HOMO is present only on the gallate moiety, whereas the LUMO is distributed only in the flavylium ring. The HOMO of 1b and 1d occur throughout the flavylium ring though only negligible HOMO/LUMO contributions are present on glucoside moiety.
The increasing order of bandgap energies in the gas phase at 1e < 1c < 1d < 1a < 1b reveals that the gallate-based compounds have the lowest bandgap energies and higher in activity. In the aqueous phase, the band gaps are higher compared to the gas phase, and the difference between the bandgap of water and gas is also represented in Table 2. One of the difficulties associated with anthocyanins as color pigments is their stability in polar solvents. When the medium changes from the gas phase to water, the only difference in the bandgap is 0.17 for 1a and 0.20 for 1b, but it is more significant for its gallates. So gallates are stable than others; hence expect higher reactivity in water (Figure 3).
Gas (eV)
Water(eV)
EHOMO
ELUMO
Band gap (ΔEgas)
EHOMO
ELUMO
Band gap (ΔEwater)
ΔEwater - ΔEgas
1a
−9.27
−6.63
2.64
−6.46
−3.65
2.81
0.17
1b
−8.80
−6.10
2.70
−6.47
−3.57
2.9
0.2
1c
−8.91
−6.36
2.55
−6.62
−3.69
2.93
0.38
1d
−9.10
−6.56
2.54
−6.71
−3.74
2.97
0.43
1e
−8.60
−6.55
2.05
−6.64
−3.78
2.86
0.81
Table 2.
FMO analysis of studied compounds in gas and water media at B3LYP/6–311 + G(d, p) level of theory.
Figure 3.
FMO of 1a, 1b, 1c, 1d, & 1e in the gas phase at B3LYP/6–311 + G(d, p) level of theory.
3.3 Radical scavenging activity
The antioxidant activities of the compounds are studied using the antioxidant mechanism described in Section 2.2.2. The BDE, IP, PA, PDE, and ETE values obtained from the corresponding mechanism are used to analyze the activity of compounds. Among the five parameters, one with the lowest value and the corresponding mechanism is followed by the compound. The parameters of antioxidant activities are represented in the gas phase and aqueous phase, respectively, in Tables 3 and 4.
1a
BDE
IP
PDE
PA
ETE
3-OH
81.56
242.73
153.33
245.94
150.12
5-OH
88.99
160.77
246.47
156.03
7-OH
90.99
162.76
246.89
158.61
3’-OH
92.17
163.94
269.82
136.85
4’-OH
83.19
154.96
246.50
151.19
5’-OH
84.51
156.28
258.11
140.90
1b
5-OH
87.97
228.97
173.50
227.47
175.01
7-OH
90.53
176.05
253.17
151.86
3’-OH
90.25
175.78
278.86
125.89
4’-OH
82.15
167.69
256.71
139.96
5’-OH
89.41
174.94
267.13
136.79
1c
5-OH
89.80
174.95
229.35
249.97
154.33
7-OH
91.99
231.55
248.88
157.61
3’-OH
91.49
231.04
273.24
132.76
4’-OH
83.12
222.67
249.81
147.81
5’-OH
84.18
223.73
260.56
138.12
5”-OH
89.16
228.71
256.98
166.80
6”-OH
83.09
222.64
266.51
131.08
7”-OH
83.60
223.15
270.08
128.02
1d
5-OH
88.91
232.11
171.30
248.31
155.10
7-OH
91.05
173.45
248.11
157.45
3’-OH
83.84
166.23
249.38
148.97
3’-OH
92.94
175.34
267.53
139.92
5’-OH
91.55
173.95
269.50
136.56
1e
3-OH
88.81
227.74
175.57
248.48
154.83
5-OH
90.88
177.65
248.24
157.15
7-OH
90.30
177.06
270.75
134.06
3’-OH
83.90
170.66
249.64
148.76
5’-OH
91.04
177.80
272.33
133.22
5”-OH
89.60
176.36
282.61
121.50
6”OH
82.80
169.56
267.24
130.06
7”-OH
83.22
169.98
271.13
126.59
Table 3.
The antioxidant mechanism study of compounds 1a, 1b, 1c, 1d, and 1e in gas using B3LYP/6–311 + G(d, p) level of theory. All values are represented in kcal/Mol.
1a
BDE
IP
PDE
PA
ETE
3-OH
80.87
201.36
13.64
37.88
177.12
5-OH
85.05
17.83
37.43
181.76
7-OH
86.13
18.91
36.98
183.28
3’-OH
85.33
18.10
49.18
170.29
4’-OH
77.52
10.30
35.27
176.39
5’-OH
81.79
14.57
43.17
172.76
1b
5-OH
86.30
200.34
20.10
37.08
183.36
7-OH
87.77
21.57
36.41
185.49
3’-OH
84.02
17.82
50.14
168.02
4’-OH
77.42
11.22
37.11
174.45
5’-OH
86.08
19.87
46.66
173.55
1c
5-OH
87.22
206.11
13.83
35.85
185.50
7-OH
89.19
15.88
35.10
188.22
3’-OH
85.39
15.16
42.42
177.10
4’-OH
78.65
11.53
34.39
178.38
5’-OH
82.09
14.16
42.42
173.80
5”-OH
84.08
13.04
51.41
166.81
6”-OH
78.66
7.47
42.22
170.58
7”-OH
81.34
10.13
45.07
170.40
1d
5-OH
85.72
204.22
15.64
36.36
155.10
7-OH
87.71
17.62
35.80
157.45
3’-OH
81.34
11.26
35.21
148.97
3’-OH
88.12
18.04
49.73
139.92
5’-OH
88.99
18.91
42.69
136.56
1e
3-OH
85.82
206.11
13.83
36.73
183.22
5-OH
87.86
15.88
36.07
185.93
7-OH
87.14
15.16
47.37
173.90
3’-OH
83.51
11.53
36.78
180.86
5’-OH
86.15
14.16
46.43
173.85
5”-OH
85.02
13.04
41.67
167.55
6”-OH
79.45
7.47
45.24
171.92
7”-OH
82.11
10.13
51.60
171.00
Table 4.
The antioxidant mechanism study of compounds 1a, 1b, 1c, 1d, and 1e in water using B3LYP/6–311 + G(d, p) level of theory. All values are represented in kcal/Mol.
Bond
5 OH
7 OH
3 OH
3’ OH
4’ OH
5’ OH
5” OH
6”OH
7”OH
1a
SD
0.027
0.022
0.025
0.061
0.018
0.032
—
—
—
DI
1.889
1.911
1.855
1.831
1.937
1.825
—
—
—
1b
SD
0.027
0.022
—
0.033
0.019
0.032
—
—
—
DI
1.885
1.903
—
1.843
1.923
1.819
—
—
—
1c
SD
0.027
0.023
—
0.032
0.020
0.032
0.0317
0.025
0.032
DI
1.888
1.901
—
1.845
1.923
1.825
1.847
1.884
1.832
1d
SD
0.026
0.022
0.026
0.032
—
0.033
—
—
—
DI
1.892
1.910
1.860
1.829
—
1.813
—
—
—
1e
SD
0.026
0.022
0.026
0.031
—
0.032
0.031
0.025
0.032
DI
1.891
1.910
1.861
1.839
—
1.824
1.850
1.888
1.830
Table 5.
The SD distribution for the O-radical and delocalization index (DI) of C-O bond computed for 1a, 1b, 1c, 1d, & 1e in the gas-phase at B3LYP/6–311 + G (d, p) level of theory.
3.3.1 Analysis of HAT mechanism
In the gas phase, all studied molecules follow the HAT mechanism because of its lower BDE values. Hence, all compounds tending to form radicals by donating hydrogen atoms in respective positions are higher in the gas phase. In the case of 1a, the positions 3-OH (81.56 kcal/mol), 4’-OH (83.19 kcal/mol), and 5’-OH (84.51 kcal/mol) have the lowest values of BDE, and hence these positions are involved in radical scavenging activity in the gas phase. For a compound possessing more than one phenolic hydroxyl group, its radical scavenging activity is determined by the one with the lowest value of BDE. Hence, in this case, 3-OH is the most active site, followed by 4’-OH and 5’-OH.
The glucose substituted derivatives of 1a, 1b, and 1d in the gas phase also follow the HAT mechanism due to its lowest value of BDEs comparing with other parameters. In 1b, 4’-OH has a higher tendency to participate in radical scavenging mechanism due to its lowest BDE value (82.15 kcal/mol) compared to other phenolic OH groups in the compound. When 4’-OH is substituted with glucose moiety or 1d, 3-OH is contributing to the radical mechanism. So in 1b and 1d radical scavenging activity is mainly through B-ring (4’-OH) and C-ring (3-OH).
As from Table 3 the antioxidant activity of compound 1c are through its phenolic hydroxyl group at 4’ OH (83.12 kcal/mol), 5’ OH (84.18 kcal/mol), 6”OH (83.09 kcal/mol), and 7” OH (83.60 kcal/mol) positions with an increasing order of 6”OH < 4’ OH < 7” OH < 5’ OH. The phenolic hydroxyl groups at 4’ OH and 5’ OH situates on the B-ring of 1a, whereas 6”OH and 7” OH at gallic acid moiety. Here, both rings, the gallate ring, and delphinidin ring moieties, contribute to the radical scavenging activity through the hydroxyl groups. Since an ester relation connects gallate and delphinidin moieties, the radicals produced in one ring do not delocalize much to another ring and acts as separate contributors to radical scavenging activity. Like that, 1e also shows antioxidant activity through 3’ OH (83.90 kcal/mol), 6” OH (82.80 kcal/mol) and 7” OH (83.22 kcal/mol). The 6” OH has a slightly lower value of BDE than the other two OH groups because the radical formed at para OH is highly stabilized through the aromatic system of gallate moiety. Similar to 1c, compound 1e also possesses radical scavenging activity through B-ring and gallic acid moiety. When comparing 1c and 1e with other molecules, when gallic acid is substituted, the number of hydroxyl groups under lower BDE values increases. Hence, the chance of enhancing activity is clear.
To explain the differences in BDE and consequently the differences in the reactivity of OH sites, the spin density distribution of radicals was calculated and presented in Table 5. The stability of radicals formed can be explained with the help of SD values; more delocalized SD means to be more stable is the radical formed. Moreover, the delocalization index is also a supporting parameter for explaining the stability of radicals created. The more stable the radical formed from an -OH bond, the more the corresponding C-O bond will be the delocalization index. The DI of C-O bonds in each radical site are calculated using Fuzzy atomic space analysis [44, 45, 46]. The SD contours of 1c are represented in Figure 4.
Figure 4.
Electronic spin density distributions and optimized structures of 1c radicals in the gas-phase at B3LYP/6–311 + G (d, p) level of theory.
3.3.2 Analysis of SET-PT mechanism
In the SET-PT mechanism, the parameters involved are IP and PDE. In all derivative IP is found to be higher in both media. The PDE values are higher in the gas phase but lower in the water medium. But the lower value in the water medium cannot be used for final judgment about contribution in antioxidant activity. In the SET-PT mechanism, the PDE comes from the second step of this mechanism, whereas the first step is the IP. Since all cases have the highest values for IP in the water medium, they have to overcome this large energy barrier of IP to reach the second step.
3.3.3 Analysis of SPLET mechanism
In water, the parameters BDE, IP, and ETE having higher enthalpy than PA and are represented in Table 4. Hence SPLET is the mechanism followed by each molecule in the water medium. In the SPLET mechanism, the heterolytic bond cleavage of the phenolic hydroxyl group is considered, and the neutral molecule is split into an anion and a proton. The numerical parameter associated with this step is PA. The anion produced donates one electron to free radical species, and the free radical receives one electron and forms an anion. The anion of free radical react with proton forms a neutral compound by leaving the anion starting compound as radical. The numerical parameter associated with this step is ETE. The values of PA are found to be lower than BDE and other parameters in all studied cases when the solvent was aqueous. In the case of 1a, 4’ OH possesses the lowest value of PA (35.27 kcal/mol), contributing to the radical scavenging mechanism.
In the case of 1b, the PA value of 7 OH (36.41 kcal/mol) has a lower value, and 5 OH (37.08 kcal/mol) and 4’ OH (37.11 kcal/mol) have valued at the nearest. When glucose at position 3 enhances the electron-donating capacity of A ring. When glucose at 4′ position called 1d, the lowest PA value at 3-OH (35.21 kcal/mol) and followed nearest at 7 OH (35.80 kcal/mol) and 5-OH (36.36 kcal/mol) also enhances the radical scavenging activity of A- ring. The lowest PA value of 1c in water is 4’ OH (34.39 kcal/mol), which is the lowest of all studied compounds in the water medium. The PA values 35.10 kcal/mol of 7 OH and 5 OH are near the 4’ OH. For 1e, the lowest value of PA at 5-OH (36.07 kcal/mol). In the water medium, the gallate moiety containing hydroxyl group does not affect radical scavenging activity due to its higher PA values. In the gas phase, a considerable contribution is provided by this group.
4. Conclusion
A theoretical study on the antioxidant activity of natural pigment delphinidin and its derivative has been evaluated. The antiradical properties of all studied molecules are finalized through an antioxidant mechanism. All compounds follow the HAT mechanism in the gas phase and the SPLET mechanism in the aqueous medium. In gas-phase gallic acid, substituted compounds possess considerable enhancement in activities by providing more hydroxyl groups of near BDEs. In the water medium, 1c posses a lower value of PA than other compounds. Frontier molecular orbital analysis also supports the radical scavenging activity of compounds. The HOMO-LUMO gap of each molecule increases when the medium changes from the gas phase to the water medium. Hence all these are more stable in water especially gallic acid-based pigments, so the stability issue of bare pigments in the solvent can be solved by its gallates.
Acknowledgments
The author, Sumayya Pottachola, expresses sincere gratitude to UGC-MANF for financial support and the central sophisticated instrumentation facility (CSIF) of the University of Calicut for Gaussian 09 software support.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"DFT, Multiwfn, Delphinidin, Radical scavenger, Gallic acid",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/77451.pdf",chapterXML:"https://mts.intechopen.com/source/xml/77451.xml",downloadPdfUrl:"/chapter/pdf-download/77451",previewPdfUrl:"/chapter/pdf-preview/77451",totalDownloads:133,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 8th 2021",dateReviewed:"May 31st 2021",datePrePublished:"July 7th 2021",datePublished:"May 18th 2022",dateFinished:"July 7th 2021",readingETA:"0",abstract:"A theoretical evaluation of the antioxidant activity of natural pigment delphinidin (1a) and derivatives 1b, 1c, 1d & 1e was performed using the DFT-B3LYP/6–311 + G (d, p) level of theory. Three potential working mechanisms, hydrogen atom transfer (HAT), stepwise electron transfer proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET), have been investigated. The physiochemical parameters, including O–H bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE), have been calculated in the gas phase and aqueous phase. The study found that the most suitable mechanism for explaining antioxidant activity is HAT in the gas phase and SPLET in the aqueous medium in this level of theory. Spin density calculation and delocalization index of studied molecules also support the radical scavenging activity. When incorporated into natural pigment delphinidin, the gallate moiety can enhance the activity and stability of the compounds.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/77451",risUrl:"/chapter/ris/77451",signatures:"Sumayya Pottachola, Arifa Kaniyantavida and Muraleedharan Karuvanthodiyil",book:{id:"11001",type:"book",title:"Density Functional Theory",subtitle:"Recent Advances, New Perspectives and Applications",fullTitle:"Density Functional Theory - Recent Advances, New Perspectives and Applications",slug:"density-functional-theory-recent-advances-new-perspectives-and-applications",publishedDate:"May 18th 2022",bookSignature:"Daniel Glossman-Mitnik",coverURL:"https://cdn.intechopen.com/books/images_new/11001.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-846-0",printIsbn:"978-1-83969-845-3",pdfIsbn:"978-1-83969-847-7",isAvailableForWebshopOrdering:!0,editors:[{id:"198499",title:"Dr.",name:"Daniel",middleName:null,surname:"Glossman-Mitnik",slug:"daniel-glossman-mitnik",fullName:"Daniel Glossman-Mitnik"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"418013",title:"Prof.",name:"Muraleedharan",middleName:null,surname:"Karuvanthodiyil",fullName:"Muraleedharan Karuvanthodiyil",slug:"muraleedharan-karuvanthodiyil",email:"cue3058@uoc.ac.in",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"418015",title:"MSc.",name:"Sumayya",middleName:null,surname:"Pottachola",fullName:"Sumayya Pottachola",slug:"sumayya-pottachola",email:"sumipc.2012@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Calicut",institutionURL:null,country:{name:"India"}}},{id:"418016",title:"MSc.",name:"Arifa",middleName:null,surname:"Kaniyantavida",fullName:"Arifa Kaniyantavida",slug:"arifa-kaniyantavida",email:"km2cd@yahoo.co.in",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Calicut",institutionURL:null,country:{name:"India"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Materials and method",level:"1"},{id:"sec_2_2",title:"2.1 Materials",level:"2"},{id:"sec_3_2",title:"2.2 Computational methodology",level:"2"},{id:"sec_3_3",title:"2.2.1 Frontier molecular orbital (FMO) analysis",level:"3"},{id:"sec_4_3",title:"2.2.2 Radical scavenging activity",level:"3"},{id:"sec_7",title:"3. Results and discussion",level:"1"},{id:"sec_7_2",title:"3.1 Conformation analysis and geometry optimization",level:"2"},{id:"sec_8_2",title:"3.2 Molecular orbital analysis",level:"2"},{id:"sec_9_2",title:"3.3 Radical scavenging activity",level:"2"},{id:"sec_9_3",title:"3.3.1 Analysis of HAT mechanism",level:"3"},{id:"sec_10_3",title:"3.3.2 Analysis of SET-PT mechanism",level:"3"},{id:"sec_11_3",title:"3.3.3 Analysis of SPLET mechanism",level:"3"},{id:"sec_14",title:"4. Conclusion",level:"1"},{id:"sec_15",title:"Acknowledgments",level:"1"},{id:"sec_18",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'M. 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While manufacturing nonwovens, some conventional textile operations, such as carding, drawing, roving, spinning, weaving or knitting, are partially or completely eliminated. For this reason the choice of fiber is very important for nonwoven manufacturers. The commonly used fibers include natural fibers (cotton, jute, flax, wool), synthetic fibers (polyester (PES), polypropylene (PP), polyamide, rayon), special fibers (glass, carbon, nanofiber, bi-component, superabsorbent fibers). 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Fiber-reinforced composite materials are lightweight, stiff, and strong. They have good fatigue and impact resistance. Their directional and overall properties can be tailored to fulfill specific needs of different end uses by changing constituent material types and fabrication parameters such as fiber volume fraction and fiber architecture. A variety of fiber architectures can be obtained by using two- (2D) and three-dimensional (3D) fabric production techniques such as weaving, knitting, braiding, stitching, and nonwoven methods. Each fiber architecture/textile form results in a specific configuration of mechanical and performance properties of the resulting composites and determines the end-use possibilities and product range. This chapter highlights the constituent materials, fabric formation techniques, production methods, as well as application areas of textile-reinforced composites. Fiber and matrix materials used for the production of composite materials are outlined. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334239",title:"Prof.",name:"Leung",middleName:null,surname:"Wai Keung",slug:"leung-wai-keung",fullName:"Leung Wai Keung",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Hong Kong",country:{name:"China"}}}]}},subseries:{item:{id:"20",type:"subseries",title:"Animal Nutrition",keywords:"Sustainable Animal Diets, Carbon Footprint, Meta Analyses",scope:"An essential part of animal production is nutrition. Animals need to receive a properly balanced diet. One of the new challenges we are now faced with is sustainable animal diets (STAND) that involve the 3 P’s (People, Planet, and Profitability). We must develop animal feed that does not compete with human food, use antibiotics, and explore new growth promoters options, such as plant extracts or compounds that promote feed efficiency (e.g., monensin, oils, enzymes, probiotics). These new feed options must also be environmentally friendly, reducing the Carbon footprint, CH4, N, and P emissions to the environment, with an adequate formulation of nutrients.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"175762",title:"Dr.",name:"Alfredo J.",middleName:null,surname:"Escribano",slug:"alfredo-j.-escribano",fullName:"Alfredo J. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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