Table of Contents

    Topic review

    Virus-Induced Neuropathogenesis

    Subjects: Clinical Neurology
    View times: 7
    Submitted by: Mayuri Shukla


    Viral infections may cause neurological disorders by directly inducing oxidative stress and interrupting immune system function, both of which contribute to neuronal death. Several reports have described the neurological manifestations in Covid-19 patients where, in severe cases of the infection, brain inflammation and encephalitis are common. Recently, extensive research-based studies have revealed and acknowledged the clinical and preventive roles of melatonin in some viral diseases. Melatonin has been shown to have antiviral properties against several viral infections which are accompanied by neurological symptoms. The beneficial properties of melatonin relate to its properties as a potent antioxidant, anti-inflammatory, and immunoregulatory molecule and its neuroprotective effects.

    1. Introduction

    Neurodegenerative diseases are incurable and affect millions of people worldwide, leaving the individuals with debilitating health conditions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases. Neurodegenerative diseases are progressive in nature and lead to degeneration and nerve cell death, ultimately causing a decline in both the central nervous (CNS) and peripheral nervous system (PNS) functions. Accumulation of intracellular misfolded and fibrillated proteins are major hallmarks of such diseases and involve the specific actions of endoplasmic reticulum (ER) stress, ubiquitin proteasome system (UPS), and phagosomes. Mutations in the mitochondrial DNA induce reactive oxygen species (ROS) production, leading to oxidative stress. Upregulation of the apoptotic signaling via the caspase cascade drives the progression of cell death [1].

    Melatonin is a neurohormone produced in and secreted by the pineal gland, especially at night. It reaches the cerebrospinal fluid (CSF) either indirectly after its release into the blood and it subsequent discharge into the third ventricle, or, more likely, by being secreted directly into the ventricle by the pinealocytes [2], from where it reaches the cerebral tissues under physiological conditions, as evidenced by in vivo scintigraphy and autoradiography [3]; from the CSF, melatonin can more readily diffuse into the neural tissue where it protect neurons and glia from damage [4]. Melatonin is also likely produced in neurons and glial cells, which may contribute to the high levels of melatonin in the CSF compared to blood concentrations. Considering these findings, CSF-derived melatonin may decelerate the progression of neurodegenerative diseases [4]. Melatonin has a wide range of neuroprotective actions by modulating the pathophysiological mechanisms and signaling pathways observed in neurodegenerative diseases [5][6]. Along with its antioxidant, immunomodulatory, anti-inflammatory, and anti-apoptotic properties, melatonin also regulates abnormal protein dynamics, mitochondrial dysfunction and altered bioenergetics [7].

    It is well documented that viral infections can lead to neurodegenerative changes, causing significant brain damage, along with neurobehavioral alterations. Viruses have evolved through their ability, over time, to impact the CNS by crossing the blood–brain barrier (BBB), leading to neuronal deficits and degeneration. The relationship between viral infections and brain disease dates back to 1385, when the link between psychosis and influenza infection was established, which became more apparent during the Spanish flu epidemic in 1918 [8] and perhaps more evident when a condition encephalitis lethargica was recognized viral antigens in the brains of infected people [9]. Additional evidence was provided when rats exposed to Japanese encephalitis virus (JEV) developed symptoms of PD [10]. Moreover, studies in infectious CNS disorders further revealed that viruses such as herpes and measles probably breach oligodendrocytes and compromise the immune system activity by altering normal cellular physiology, resulting in the demyelination of neurons, as observed in multiple sclerosis, in sclerosing panencephalitis and in neuromyelitis optica, which are chronic autoimmune demyelinating diseases [11]. Additionally, potential links have been established between herpes simplex virus (associated with APOE-e4 allele) [12][13] and cytomegalovirus infection with inflammatory responses [14]. As human immunodeficiency virus (HIV) infection compromises the immune system, affected individuals become more susceptible to infections and diseases such as in HIV encephalopathy, a viral infection that causes neurodegenerative changes which are attributed to its ability to exploit the BBB, leading to dementia, which corresponds to the rate of spread of infection along with remarkable amyloid plaque formation [15]; this increases the risk of developing AD. Regarding PD, as the basal ganglia is an assailable target of HIV, infected subjects have a greater risk of developing this devastating condition [16]. In this context, apart from neurodegenerative diseases, much information is currently being gathered on investigations into the preventive roles of melatonin in patients affected by viral diseases like Covid-19 [17][18][19][20][21][22].

    2. Therapeutic Role of Melatonin on Post Infection Complications of Viral Induced Neuropathogenesis

    2.1. Melatonin and Anosmia

    Olfactory sensitivity exhibits a diurnal rhythm and the presence of melatonin receptor mRNAs and melatonin synthesis enzymes in the olfactory bulb affirms the possibility that melatonin is locally synthesized in the olfactory bulb [23]. Melatonin is widely known to inhibit neuronal apoptosis. In the olfactory bulb mucosae of rats, melatonin decreased the activity of caspase-3 and BAX and upregulated the expression of BCL-2, which is known to inhibit apoptosis by preserving the integrity of the mitochondrial membrane and which also inactivates BAX and other pro-apoptotic proteins [24]. Rodent studies have pointed out that GABAergic cells stimulate the production of interferons are essential for odor detection, where these cells exert a tonic inhibition that regulates the sensitivity of odor perception, as demonstrated in the mammalian brain [25]. Interestingly, modulation of the GABAergic system by melatonin might suggest the presence of a pathway for the neuroprotective effects of melatonin, given that melatonin impacts the circadian rhythm of endogenous GABAergic mechanisms [26][27]. Some anesthetic studies in humans have indicated a correlation between the levels of serum melatonin and olfactory identification impairment [28], which substantiates the involvement of melatonin in anosmia-like conditions.

    2.2. Melatonin and Myelination

    A study in a rodent model inoculated by the neuro-adapted John Howard Mueller (JHM) strain of mouse hepatitis virus (JHMV) has shown the development of an acute encephalomyelitis which disseminates throughout the brain parenchyma, causing demyelination and chronic neuroinflammation. The T cell chemoattractant chemokine CXCL10 (interferon-inducible protein IP-10) serves to recruit activated T and B lymphocytes expressing CXC chemokine receptor 3 (CXCR3), the receptor for CXCL10. Investigations have revealed that CXCL10 expression in the CNS is responsible for regulation of the JHMV viral replication and its uninterrupted expression leads to demyelination through CD4+ T-cell-induced enhancement of neuroinflammation via IFN-γ-mediated expression of other chemokines [29]. In this context, it has been reported that melatonin is involved in the regulation of CXCL10 production [30]. Melatonin also inhibits demyelination and increases remyelination, suggesting its local regulation in white matter astrocytes by serotonin availability and apolipoprotein E4 [31]. Melatonin stimulates oligodendroglia-enhanced remyelination by increasing pyruvate dehydrogenase kinases 4 (PDK4) expression and N-acetylaspartate (NAA) levels with a simultaneous reduction in inflammatory mediators in a mouse model of multiple sclerosis [32]. Moreover, multiple sclerosis is a chronic, progressive, inflammatory autoimmune disease of the myelin sheath. It has been recently documented that melatonin displays neuroprotective effects during both remyelination and demyelination stages in a rodent model of multiple sclerosis [33].

    2.3. Melatonin and Myalgia

    Myalgias are defined as muscle aches presenting as a sharp sporadic ache or a constant and deep ache. They are common in patients exposed to viral infections like coronaviruses and influenza. Nearly 30–40% of Covid-19 patients display myalgia as an early symptom [34][35]. The common underlying pathogenic mechanisms include oxidative stress and inflammation. In general, melatonin availability has been significantly associated with increased muscle strength in the average elderly population [36]. The results of one study confirmed the beneficial effects of melatonin in age-related muscle weakness [37]. Melatonin, received in a dose- and time-dependent manner, also reduced fibromyalgia-related musculoskeletal damage. Nonetheless, the therapeutic benefits of melatonin have not been thoroughly evaluated in several pain syndromes like fibromyalgia, headaches and chronic back pain [38].

    2.4. Melatonin and Hypoxic Ischemia/Stroke

    Hypoxic-ischemia often causes serious brain damage. Accumulating evidence has suggested that the neuroimaging features of hospitalized Covid-19 patients are usually dominated by acute ischemic infarction and intracranial hemorrhages [39]. Areas of the brain which may be preferentially affected by hypoxic-ischemic encephalopathy include the cerebral cortex, watershed regions between the anterior and middle cerebral artery and middle and posterior cerebral artery territories, basal ganglia, hippocampi, thalamus, cerebellum, and deep white matter [40]. Melatonin may potentially be useful in the treatment of neurodegenerative conditions that may involve free radical production, such as perinatal hypoxia. In this particular experiment, exogenously administered melatonin in animals effectively protected against brain injury by oxidative stress [41]. Increasing evidence has shown that, in animal stroke models, administering melatonin significantly reduces infarct volume, edema, and oxidative damage and improves electrophysiological and behavioral performance. Melatonin has shown neuroprotection in cerebral ischemia in acute, sub-acute, as well as chronic stages. In addition to its potent antioxidant properties, melatonin exerts antiapoptotic, antiexcitotoxic, anti-inflammatory effects and promotes mitochondrial functions in animals with cerebral ischemia [42]. Furthermore, in a neonatal rat model of stroke, melatonin increased myelin basic protein immunoreactivity in the cingulum along with increment in the mature oligodendrocytes, thus promoting myelination in the white matter with a subsequent reduction in inflammation [43]. Melatonin regulates the immunogenic cascade and inflammatory signaling in ischemic damage to the brain induced by stroke [44]. Clinical investigation in stroke patients revealed the therapeutic efficacy of melatonin administration by reduction in the oxidative response and increase in the survival rate of the patients in the intervention groups [45].

    2.5. Melatonin and Prion Diseases

    Viral infections can lead to prion diseases, which are pathological conditions associated with neuronal damage and associated behavioral disorders. Melatonin significantly alleviated PrPc induced apoptosis and mitochondrial fragmentation and dysfunction, prevented the suppression of ATP and reduced the overproduction of ROS in N2A cell cultures, thus alleviating neuronal damage [46], which is suggestive of melatonin’s use in the treatment of prion diseases. Sleep disruption is a prevalent clinical feature in many neurodegenerative disorders, including human prion diseases. Fatal familial insomnia (FFI) is an inherited prion disease that mainly affects the thalamus. The thalamus is the part of the brain that controls the sleep–wake cycle, but is also known as the “relay center” of the brain because it helps the different parts of the brain communicate with each other [47]. A decrease in the levels of serum melatonin and corresponding disturbances in sleep patterns are observed in FFI patients [48]. Based on this information, it can be speculated that a planned timely daily dose of melatonin might improve sleep parameters in such patients.

    2.6. Melatonin and Guillain–Barré Syndrome

    Several reports have described Covid-19 patients as suffering from GBS [49]. GBS is triggered by a viral or bacterial infection where the body’s own immune system attacks the nerves. Symptoms start as weakness and tingling in the feet and legs that spreads to the upper body, and later, paralysis can also occur. GBS has several forms; of them, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is the most common, in which muscle weakness starts in the lower part of the body and spreads upward. Miller Fisher syndrome (MFS), in which paralysis starts in the eyes, and acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN), are less common forms. Sleep and psychiatric disturbances, along with anxiety, are common manifestations of GBS [50]. As such, low-level inflammation induced by neurotropic viruses increase the risk of psychiatric disorders [51]. Additionally, neuropathic pain also accounts for the neurological complication associated with this disorder [52]. It has been shown in preclinical studies that melatonin may be useful in the management of neuropathic pain [53]. Disturbances in the melatonin secretion is a characteristic feature in many psychiatric disorders [54] and exogenous melatonin has proven useful in patients with varied forms of psychiatric disturbances [55].

    2.7. Melatonin and Neurotransmitters

    Virus-induced pathogenesis also involves glutamate dysfunction, leading to brain damage [56]. Human coronavirus strain OC43 affects human glial and neuronal cells. Expression of the glial glutamate transporter 1 is responsible for glutamate homeostasis, which has been shown to decrease following this viral infection. One report demonstrated that inhibition of glutamate excitotoxicity using a 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propranoic acid (AMPA) receptor antagonist (GYKI-52466) improved clinical scores related to paralysis and motor disabilities in S mutant virus-infected mice, as well as protecting the CNS from neuronal dysfunctions [51]. Melatonin has dynamic neuroprotective properties. In an HT22 mouse hippocampal cell line, melatonin reduced glutamate-induced oxytosis via its antioxidant action targeted at the mitochondria [57]. Recently, targeting glutamate with melatonin has been discussed for its possible therapeutic benefits in the treatment of anxiety [58], which is yet another complication observed in virus-infected patients.

    Viruses such as wild type vesicular stomatitis virus (VSV) can rapidly and selectively infect and destroy serotonin neurons in young mice and rats. A subsequent immune system-mediated response eliminates all trace of the virus from the brain, leaving a permanent reduction in serotonin neurons, with consequent behavioral alterations [59], with no viral element remaining. The neurotransmitter and behavioral changes resulting from this initial infection may last for the lifetime of the organism, despite the lack of any trace of the virus in the brain, and with little detectable viral-mediated neuropathology evident by standard screening methods at the end of life. In this context, it has been shown that melatonin regulates (via its deacetylation to 5-methoxytryptamine) CYP2D-mediated synthesis of serotonin from 5-methoxytryptamine in the brain regions; hippocampus, cortex, striatum, nucleus accumbens, hypothalamus and thalamus as well as the medulla oblongata and cerebellum of the male Wistar rat, which are well recognized as the targeted pharmacological action of melatonin [60].

    The entry is from 10.3390/antiox10010047


    1. Jellinger, K.A. Basic mechanisms of neurodegeneration: A critical update. J. Cell Mol. Med. 2010, 14, 457–487.
    2. Tricoire, H.; Moller, M.; Chemineau, P.; Malpaux, B. Origin of cerebrospinal fluid melatonin and possible function in the integration of photoperiod. Reprod. Suppl. 2003, 61, 311–321.
    3. Legros, C.; Chesneau, D.; Boutin, J.A.; Barc, C.; Malpaux, B. Melatonin from cerebrospinal fluid but not from blood reaches sheep cerebral tissues under physiological conditions. J. Neuroendocrinol. 2014, 26, 151–163.
    4. Reiter, R.J.; Tan, D.X.; Kim, S.J.; Cruz, M.H. Delivery of pineal melatonin to the brain and SCN: Role of canaliculi, cerebrospinal fluid, tanycytes and Virchow-Robin perivascular spaces. Brain Struct. Funct. 2014, 219, 1873–1887.
    5. Shukla, M.; Govitrapong, P.; Boontem, P.; Reiter, R.J.; Satayavivad, J. Mechanisms of melatonin in alleviating Alzheimer’s disease. Curr. Neuropharmacol. 2017, 15, 1010–1031.
    6. Chen, D.; Zhang, T.; Lee, T.H. Cellular mechanisms of melatonin: Insight from neurodegenerative diseases. Biomolecules 2020, 10, 1158.
    7. Shukla, M.; Chinchalongporn, V.; Govitrapong, P.; Reiter, R.J. The role of melatonin in targeting cell signaling pathways in neurodegeneration. Ann. N. Y. Acad. Sci. 2019, 1443, 75–96.
    8. Menniger, K.A. Psychoses associated with influenza: 2. Specific data. An expository analysis. Arch. Neurol. Psychiatry 1919, 2, 291–337.
    9. Gamboa, E.T.; Wolf, A.; Yahr, M.D.; Harter, D.H.; Duffy, P.E.; Barden, H.; Hsu, K.C. Influenza virus antigen in postencephalitic parkinsonism brain. Detection by immunofluorescence. Arch. Neurol 1974, 31, 228–232.
    10. Ogata, A.; Tashiro, K.; Nukuzuma, S.; Nagashima, K.; Hall, W.W. A rat model of Parkinson’s disease induced by Japanese encephalitis virus. J. Neurovirol. 1997, 3, 141–147.
    11. Owens, G.P.; Gilden, D.; Burgoon, M.P.; Yu, X.; Bennett, J.L. Viruses and multiple sclerosis. Neuroscientist 2011, 17, 659–676.
    12. Itzhaki, R.F.; Lin, W.R.; Shang, D.; Wilcock, G.K.; Faragher, B.; Jamieson, G.A. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 1997, 349, 241–244.
    13. Itzhaki, R.F. Herpes simplex virus type 1 and Alzheimer’s disease: Increasing evidence for a major role of the virus. Front. Aging Neurosci. 2014, 6, 202.
    14. Lurain, N.S.; Hanson, B.A.; Martinson, J.; Leurgans, S.E.; Landay, A.L.; Bennett, D.A.; Schneider, J.A. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease. J. Infect. Dis. 2013, 208, 564–572.
    15. Canet, G.; Dias, C.; Gabelle, A.; Simonin, Y.; Gosselet, F.; Marchi, N.; Makinson, A.; Tuaillon, E.; Van de Perre, P.; Givalois, L.; et al. HIV neuroinfection and Alzheimer’s disease: Similarities and potential links? Front. Cell Neurosci. 2018, 12, 307.
    16. Dehner, L.F.; Spitz, M.; Pereira, J.S. Parkinsonism in HIV infected patients during antiretroviral therapy—data from a Brazilian tertiary hospital. Braz. J. Infect. Dis. 2016, 20, 499–501.
    17. Zhang, R.; Wang, X.; Ni, L.; Di, X.; Ma, B.; Niu, S.; Liu, C.; Reiter, R.J. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020, 250, 117583.
    18. Rodriguez-Rubio, M.; Figueira, J.C.; Acuna-Castroviejo, D.; Borobia, A.M.; Escames, G.; de la Oliva, P. A phase 2, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensive care unit (MelCOVID study): A structured summary of a study protocol for a randomized controlled trial. Trials 2020, 21, 699.
    19. Ziaei, A.; Davoodian, P.; Dadvand, H.; Safa, O.; Hassanipour, S.; Omidi, M.; Masjedi, M.; Mahmoudikia, F.; Rafiee, B.; Fathalipour, M. Evaluation of the efficacy and safety of melatonin in moderately ill patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials 2020, 21, 882.
    20. Garcia, I.G.; Rodriguez-Rubio, M.; Mariblanca, A.R.; de Soto, L.M.; Garcia, L.D.; Villatoro, J.M.; Parada, J.Q.; Meseguer, E.S.; Rosales, M.J.; Gonzalez, J.; et al. A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial. Trials 2020, 21, 466.
    21. Ramlall, V.; Zucker, J.; Tatonetti, N. Melatonin is significantly associated with survival of intubated COVID-19 patients. medRxiv 2020.
    22. Acuna-Castroviejo, D.; Escames, G.; Figueira, J.C.; de la Oliva, P.; Borobia, A.M.; Acuna-Fernandez, C. Clinical trial to test the efficacy of melatonin in COVID-19. J. Pineal Res. 2020, 69, e12683.
    23. Corthell, J.T.; Olcese, J.; Trombley, P.Q. Melatonin in the mammalian olfactory bulb. Neuroscience 2014, 261, 74–84.
    24. Koc, S.; Cayli, S.; Aksakal, C.; Ocakli, S.; Soyalic, H.; Somuk, B.T.; Yuce, S. Protective effects of melatonin and selenium against apoptosis of olfactory sensory neurons: A rat model study. Am. J. Rhinol. Allergy 2016, 30, 62–66.
    25. Murueta-Goyena, A.; Andikoetxea, A.; Gomez-Esteban, J.C.; Gabilondo, I. Contribution of the GABAergic system to non-motor manifestations in premotor and early stages of parkinson’s disease. Front. Pharmacol. 2019, 10, 1294.
    26. Rosenstein, R.E.; Cardinali, D.P. Central gabaergic mechanisms as targets for melatonin activity in brain. Neurochem. Int. 1990, 17, 373–379.
    27. Cheng, X.P.; Sun, H.; Ye, Z.Y.; Zhou, J.N. Melatonin modulates the GABAergic response in cultured rat hippocampal neurons. J. Pharmacol. Sci. 2012, 119, 177–185.
    28. Saravanan, B.; Kundra, P.; Mishra, S.K.; Surianarayanan, G.; Parida, P.K. Effect of anaesthetic agents on olfactory threshold and identification—A single blinded randomised controlled study. Indian J. Anaesth. 2018, 62, 592–598.
    29. Skinner, D.; Marro, B.S.; Lane, T.E. Chemokine CXCL10 and coronavirus-induced neurologic disease. Viral Immunol. 2019, 32, 25–37.
    30. Hosokawa, I.; Hosokawa, Y.; Shindo, S.; Ozaki, K.; Matsuo, T. Melatonin inhibits CXCL10 and MMP-1 production in IL-1β-stimulated human periodontal ligament Cells. Inflammation 2016, 39, 1520–1526.
    31. Anderson, G.; Rodriguez, M. Multiple sclerosis: The role of melatonin and N-acetylserotonin. Mult. Scler. Relat. Disord. 2015, 4, 112–123.
    32. Ghareghani, M.; Scavo, L.; Jand, Y.; Farhadi, N.; Sadeghi, H.; Ghanbari, A.; Mondello, S.; Arnoult, D.; Gharaghani, S.; Zibara, K. Melatonin therapy modulates cerebral metabolism and enhances remyelination by increasing PDK4 in a mouse model of multiple sclerosis. Front. Pharmacol. 2019, 10, 147.
    33. Abo Taleb, H.A.; Alghamdi, B.S. Neuroprotective effects of melatonin during demyelination and remyelination stages in a mouse model of multiple sclerosis. J. Mol. Neurosci. 2020, 70, 386–402.
    34. Kucuk, A.; Cumhur Cure, M.; Cure, E. Can COVID-19 cause myalgia with a completely different mechanism? A hypothesis. Clin. Rheumatol. 2020, 39, 2103–2104.
    35. Lippi, G.; Wong, J.; Henry, B.M. Myalgia may not be associated with severity of coronavirus disease 2019 (COVID-19). World J. Emerg. Med. 2020, 11, 193–194.
    36. Obayashi, K.; Saeki, K.; Maegawa, T.; Iwamoto, J.; Sakai, T.; Otaki, N.; Kataoka, H.; Kurumatani, N. Melatonin secretion and muscle strength in elderly individuals: A cross-sectional study of the HEIJO-KYO Cohort. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2016, 71, 1235–1240.
    37. Favero, G.; Franceschetti, L.; Bonomini, F.; Rodella, L.F.; Rezzani, R. Melatonin as an anti-inflammatory agent modulating inflammasome activation. Int. J. Endocrinol. 2017, 2017, 1835195.
    38. Danilov, A.; Kurganova, J. Melatonin in chronic pain syndromes. Pain Ther. 2016, 5, 1–17.
    39. Valderrama, E.V.; Humbert, K.; Lord, A.; Frontera, J.; Yaghi, S. Severe acute respiratory syndrome coronavirus 2 infection and ischemic stroke. Stroke 2020, 51, e124–e127.
    40. Bathla, G.; Hegde, A.N. MRI and CT appearances in metabolic encephalopathies due to systemic diseases in adults. Clin. Radiol. 2013, 68, 545–554.
    41. Tutunculer, F.; Eskiocak, S.; Basaran, U.N.; Ekuklu, G.; Ayvaz, S.; Vatansever, U. The protective role of melatonin in experimental hypoxic brain damage. Pediatr. Int. 2005, 47, 434–439.
    42. Lin, H.W.; Lee, E.J. Effects of melatonin in experimental stroke models in acute, sub-acute, and chronic stages. Neuropsychiatr. Dis. Treat. 2009, 5, 157–162.
    43. Villapol, S.; Fau, S.; Renolleau, S.; Biran, V.; Charriaut-Marlangue, C.; Baud, O. Melatonin promotes myelination by decreasing white matter inflammation after neonatal stroke. Pediatr. Res. 2011, 69, 51–55.
    44. Andrabi, S.S.; Parvez, S.; Tabassum, H. Melatonin and ischemic stroke: Mechanistic roles and action. Adv. Pharmacol. Sci. 2015, 2015, 384750.
    45. Ramos, E.; Farre-Alins, V.; Egea, J.; Lopez-Munoz, F.; Reiter, R.J.; Romero, A. Melatonin’s efficacy in stroke patients; a matter of dose? A systematic review. Toxicol. Appl. Pharmacol. 2020, 392, 114933.
    46. Zhang, X.; Zhao, D.; Wu, W.; Ali Shah, S.Z.; Lai, M.; Yang, D.; Li, J.; Guan, Z.; Li, W.; Gao, H.; et al. Melatonin regulates mitochondrial dynamics and alleviates neuron damage in prion diseases. Aging 2020, 12, 11139–11151.
    47. Llorens, F.; Zarranz, J.J.; Fischer, A.; Zerr, I.; Ferrer, I. Fatal familial insomnia: Clinical aspects and molecular alterations. Curr. Neurol. Neurosci. Rep. 2017, 17, 30.
    48. Portaluppi, F.; Cortelli, P.; Avoni, P.; Vergnani, L.; Maltoni, P.; Pavani, A.; Sforza, E.; Degli Uberti, E.C.; Gambetti, P.; Lugaresi, E. Progressive disruption of the circadian rhythm of melatonin in fatal familial insomnia. J. Clin. Endocrinol. Metab. 1994, 78, 1075–1078.
    49. Coen, M.; Jeanson, G.; Culebras Almeida, L.A.; Hubers, A.; Stierlin, F.; Najjar, I.; Ongaro, M.; Moulin, K.; Makrygianni, M.; Leemann, B.; et al. Guillain-Barre syndrome as a complication of SARS-CoV-2 infection. Brain Behav. Immun. 2020, 87, 111–112.
    50. Karkare, K.; Sinha, S.; Taly, A.B.; Rao, S. Prevalence and profile of sleep disturbances in Guillain-Barre Syndrome: A prospective questionnaire-based study during 10 days of hospitalization. Acta Neurol. Scand. 2013, 127, 116–123.
    51. Bechter, K. Virus infection as a cause of inflammation in psychiatric disorders. Mod. Trends Pharmacopsychiatry 2013, 28, 49–60.
    52. Bahnasy, W.S.; El-Heneedy, Y.A.E.; El-Shamy, A.M.; Badr, M.Y.; Amer, R.A.; Ibrahim, I.S.E. Sleep and psychiatric abnormalities in Gullian Barre Syndrome. Egypt J. Neurol. Psychiatr. Neurosurg. 2018, 54, 5.
    53. Kuthati, Y.; Lin, S.H.; Chen, I.J.; Wong, C.S. Melatonin and their analogs as a potential use in the management of Neuropathic pain. J. Formos. Med. Assoc. 2019, 118, 1177–1186.
    54. Pacchierotti, C.; Iapichino, S.; Bossini, L.; Pieraccini, F.; Castrogiovanni, P. Melatonin in psychiatric disorders: A review on the melatonin involvement in psychiatry. Front. Neuroendocrinol. 2001, 22, 18–32.
    55. Geoffroy, P.A.; Micoulaud Franchi, J.A.; Lopez, R.; Schroder, C.M.; membres du consensus Mélatonine SFRMS. The use of melatonin in adult psychiatric disorders: Expert recommendations by the French institute of medical research on sleep (SFRMS). Encephale 2019, 45, 413–423.
    56. Van den Pol, A.N. Viral infection leading to brain dysfunction: More prevalent than appreciated? Neuron 2009, 64, 17–20.
    57. Herrera, F.; Martin, V.; García-Santos, G.; Rodriguez-Blanco, J.; Antolín, I.; Rodriguez, C. Melatonin prevents glutamate-induced oxytosis in the HT22 mouse hippocampal cell line through an antioxidant effect specifically targeting mitochondria. J. Neurochem. 2007, 100, 736–746.
    58. Dhangar, R.R.; Kale, P.P.; Kadu, P.K.; Prabhavalkar, K. Possible benefits of considering glutamate with melatonin or orexin or oxytocin as a combination approach in the treatment of anxiety. Curr. Pharmacol. Rep. 2020, 6, 1–7.
    59. Mohammed, A.K.H.; Maehlen, J.; Magnusson, O.; Fonnum, F.; Kristensson, K. Persistent changes in behaviour and brain serotonin during ageing in rats subjected to infant nasal virus infection. Neurobiol. Aging 1992, 13, 83–87.
    60. Haduch, A.; Bromek, E.; Wojcikowski, J.; Golembiowska, K.; Daniel, W.A. Melatonin supports CYP2D-mediated serotonin synthesis in the brain. Drug Metab. Dispos. 2016, 44, 445–452.