High doses of melatonin as a potential therapeutic tool for the neurologic sequels of covid-19 infection
Melatonin and the neurologic sequels of covid-19 infection
Keywords:
allometry, COVID-19, cytoprotection, inflammation, melatonin, stroke
Abstract
The therapeutic potential of melatonin as an agent to counteract the consequences of COVID-19 infections is due to its wide-ranging effects as a powerful antioxidant, anti-inflammatory, and immunostimulant, as well as to a possible antiviral action. In view of the recently reported evidence on the occurrence of neurological sequels in COVID-19-infected patients, another putative application of melatonin emerges based on its neuroprotective properties. In this manuscript a brief discussion of melatonin activity in animal models of ischemic and hemorrhagic stroke and the allometric calculations of the possible human equivalent doses are made. Based on the safety of melatonin, and in order to maximize its therapeutic opportunity, doses of 100 - 300 mg p.o. or i.v. are proposed.
References
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2 Tan DX, Hardeland R (2020) Potential utility of melatonin in deadly infectious diseases related to the overreaction of innate immune response and destructive inflammation: focus on COVID-19. Melatonin Res. 3: 120-143. doi: 10.32794/mr11250052.
3 Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. doi: 10.1001/jamaneurol.2020.1127.
4 Li YC, Bai WZ, Hashikawa T (2020) The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J. Med. Virol. doi: 10.1002/jmv.25728 doi: 10.1002/jmv.25728.
5 Kaji R (2019) Global burden of neurological diseases highlights stroke. Nat. Rev. Neurol. 15: 371-372. doi: 10.1038/s41582-019-0208-y.
6 Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, et al. (2020) COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 250: 117583. doi: 10.1016/j.lfs.2020.117583.
7 Maestroni GJ (1999) Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer. Adv. Exp. Med. Biol. 467: 217-226. DOI: 10.1007/978-1-4615-4709-9_28.
8 Anderson G, Maes M, Markus RP, Rodriguez M (2015) Ebola virus: melatonin as a readily available treatment option. J. Med. Virol. 87: 537-543. doi: 10.1002/jmv.24130.
9 Cardinali DP (2019) Melatonin: clinical perspectives in neurodegeneration. Front. Endocrinol. (Lausanne) 10: 480. doi: 10.3389/fendo.2019.00480.
10 Ben-Nathan D, Maestroni GJ, Lustig S, Conti A (1995) Protective effects of melatonin in mice infected with encephalitis viruses. Arch. Virol. 140: 223-30. DOI: 10.1007/bf01309858.
11 Hardeland R (2018) Melatonin and inflammation-Story of a double-edged blade. J. Pineal Res. 65: e12525. doi: 10.1111/jpi.12525.
12 Xia Y, Chen S, Zeng S, Zhao Y, Zhu C, Deng B, et al. (2018) Melatonin in macrophage biology: current understanding and future perspectives. J. Pineal Res. 66 (2): e12547. doi: 10.1111/jpi.12547.
13 Pedrosa AM, Weinlich R, Mognol GP, Robbs BK, Viola JP, Campa A, et al. (2010) Melatonin protects CD4+ T cells from activation-induced cell death by blocking NFAT-mediated CD95 ligand upregulation. J. Immunol. 184: 3487-3494. doi: 10.4049/jimmunol.0902961.
14 Shang Y, Xu SP, Wu Y, Jiang YX, Wu ZY, Yuan SY, et al. (2009) Melatonin reduces acute lung injury in endotoxemic rats. Chin. Med. J. (Engl ) 122: 1388-1393.
15 Deng WG, Tang ST, Tseng HP, Wu KK (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108: 518-524. DOI: 10.1182/blood-2005-09-3691.
16 Ahmadi Z, Ashrafizadeh M (2020) Melatonin as a potential modulator of Nrf2. Fundam. Clin. Pharmaco.l 34: 11-19. doi: 10.1111/fcp.12498.
17 Habtemariam S, Daglia M, Sureda A, Selamoglu Z, Gulhan MF, Nabavi SM (2017) Melatonin and respiratory diseases: a review. Curr. Top. Med. Chem. 17: 467-488. DOI: 10.2174/1568026616666160824120338.
18 Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, et al. (2015) Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J. Pineal Res. 59: 403-419. doi: 10.1111/jpi.12267.
19 Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J. Pineal Res. 51: 1-16. doi: 10.1111/j.1600-079X.2011.00916.x.
20 Reiter RJ, Tan DX, Rosales-Corral S, Galano A, Jou MJ, Acuña-Castroviejo D (2018) Melatonin mitigates mitochondrial meltdown: interactions with SIRT3. Int. J. Mol. Sci. 19 (8): pii: E2439. doi: 10.3390/ijms19082439.
21 Huang Q, Riviere JE (2014) The application of allometric scaling principles to predict pharmacokinetic parameters across species. Expert. Opin. Drug Metab. Toxicol. 10: 1241-1253.
22 Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J. 22: 659-661. DOI: 10.1096/fj.07-9574LSF.
23 Ersahin M, Toklu HZ, Cetinel S, Yuksel M, Yegen BC, Sener G (2009) Melatonin reduces experimental subarachnoid hemorrhage-induced oxidative brain damage and neurological symptoms. J. Pineal Res. 46: 324-332. doi: 10.1111/j.1600-079X.2009.00664.x.
24 Wang Z, Ma C, Meng CJ, Zhu GQ, Sun XB, Huo L, et al. (2012) Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model. J. Pineal Res. 53: 129-137. doi: 10.1111/j.1600-079X.2012.00978.x.
25 Ayer RE, Sugawara T, Chen W, Tong W, Zhang JH (2008) Melatonin decreases mortality following severe subarachnoid hemorrhage. J. Pineal Res. 44: 197-204. doi: 10.1111/j.1600-079X.2007.00508.x.
26 Chen J, Wang L, Wu C, Hu Q, Gu C, Yan F, et al. (2014) Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage. J. Pineal Res. 56: 12-19. doi: 10.1111/jpi.12086.
27 Chen J, Chen G, Li J, Qian C, Mo H, Gu C, et al. (2014) Melatonin attenuates inflammatory response-induced brain edema in early brain injury following a subarachnoid hemorrhage: a possible role for the regulation of pro-inflammatory cytokines. J. Pineal Res. 57: 340-347. doi: 10.1111/jpi.12173.
28 Wang Z, Wu L, You W, Ji C, Chen G (2013) Melatonin alleviates secondary brain damage and neurobehavioral dysfunction after experimental subarachnoid hemorrhage: possible involvement of TLR4-mediated inflammatory pathway. J. Pineal Res. 55: 399-408. doi: 10.1111/jpi.12087.
29 Fang Q, Chen G, Zhu W, Dong W, Wang Z (2009) Influence of melatonin on cerebrovascular proinflammatory mediators expression and oxidative stress following subarachnoid hemorrhage in rabbits. Mediators Inflamm. 2009: 426346. doi: 10.1155/2009/426346.
30 Ueda Y, Masuda T, Ishida A, Misumi S, Shimizu Y, Jung CG, et al. (2014) Enhanced electrical responsiveness in the cerebral cortex with oral melatonin administration after a small hemorrhage near the internal capsule in rats. J. Neurosci. Res. 92: 1499-1508. doi: 10.1002/jnr.23434.
31 Rojas H, Lekic T, Chen W, Jadhav V, Titova E, Martin RD et al. (2008) The antioxidant effects of melatonin after intracerebral hemorrhage in rats. Acta. Neurochir. Suppl 105: 19-21. DOI: 10.1007/978-3-211-09469-3_4.
32 Lekic T, Hartman R, Rojas H, Manaenko A, Chen W, Ayer R, et al. (2010) Protective effect of melatonin upon neuropathology, striatal function, and memory ability after intracerebral hemorrhage in rats. J. Neurotrauma 27: 627-637. doi: 10.1089/neu.2009.1163.
33 Borlongan CV, Yamamoto M, Takei N, Kumazaki M, Ungsuparkorn C, Hida H, et al. (2000) Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia. FASEB J. 14: 1307-1317. DOI: 10.1096/fj.14.10.1307.
34 Kondoh T, Uneyama H, Nishino H, Torii K (2002) Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats. Life Sci. 72: 583-590. DOI: 10.1016/s0024-3205(02)02256-7.
35 Lin YW, Chen TY, Hung CY, Tai SH, Huang SY, Chang CC, et al. (2018) Melatonin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress. Int. J. Mol. Med. 42: 182-192. doi: 10.3892/ijmm.2018.3607.
36 Lee MY, Kuan YH, Chen HY, Chen TY, Chen ST, Huang CC, et al. (2007) Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats. J. Pineal Res. 42: 297-309. DOI: 10.1111/j.1600-079X.2007.00420.x.
37 Lee EJ, Wu TS, Lee MY, Chen TY, Tsai YY, Chuang JI, et al. (2004) Delayed treatment with melatonin enhances electrophysiological recovery following transient focal cerebral ischemia in rats. J. Pineal Res. 36: 33-42. DOI: 10.1046/j.1600-079x.2003.00093.x.
38 Alonso-Alconada D, Alvarez A, Lacalle J, Hilario E (2012) Histological study of the protective effect of melatonin on neural cells after neonatal hypoxia-ischemia. Histol. Histopathol. 27: 771-783. doi: 10.14670/HH-27.771.
39 Letechipia-Vallejo G, Lopez-Loeza E, Espinoza-Gonzalez V, Gonzalez-Burgos I, Olvera-Cortes ME, Morali G, et al. (2007) Long-term morphological and functional evaluation of the neuroprotective effects of post-ischemic treatment with melatonin in rats. J. Pineal Res. 42: 138-146. DOI: 10.1111/j.1600-079X.2006.00395.x.
40 Cuzzocrea S, Costantino G, Gitto E, Mazzon E, Fulia F, Serraino I, et al. (2000) Protective effects of melatonin in ischemic brain injury. J. Pineal Res. 29: 217-27. DOI: 10.1034/j.1600-0633.2002.290404.x.
41 Sun FY, Lin X, Mao LZ, Ge WH, Zhang LM, Huang YL, et al. (2002) Neuroprotection by melatonin against ischemic neuronal injury associated with modulation of DNA damage and repair in the rat following a transient cerebral ischemia. J. Pineal Res. 33: 48-56. DOI: 10.1034/j.1600-079x.2002.01891.x.
42 Pei Z, Pang SF, Cheung RT (2003) Administration of melatonin after onset of ischemia reduces the volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model. Stroke 34: 770-775. DOI: 10.1161/01.STR.0000057460.14810.3E.
43 Yang Y, Jiang S, Dong Y, Fan C, Zhao L, Yang X, et al. (2015) Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. J. Pineal Res. 58: 61-70. doi: 10.1111/jpi.12193.
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Published
2020-06-15
How to Cite
[1]
Cardinali, D.P. 2020. High doses of melatonin as a potential therapeutic tool for the neurologic sequels of covid-19 infection. Melatonin Research. 3, 3 (Jun. 2020), 311-317. DOI:https://doi.org/https://doi.org/10.32794/mr11250064.
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