Melatonin and Parkinson Disease: Current Status and Future Perspectives for Molecular Mechanisms

Tamtaji, Omid Reza; Reíter, Russel J.; Alipoor, Reza; Dadgostar, Ehsan; Kouchaki, Ebrahim; Asemi, Zatollah

doi:10.1007/s10571-019-00720-5

Cited by 50 publications

(33 citation statements)

References 128 publications

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“…Melatonin is classified as the mitochondrially targeted antioxidant [ 113 ]. Thus, reduced melatonin levels are associated with several diseases including neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis), heart disease, breast and prostate cancers, multiple ovarian cysts, diabetes, and systemic metabolic disorders [ 114 , 115 , 116 , 117 ]. Conversely, melatonin treatment has beneficial effects on most of these diseases [ 118 , 119 , 120 ].…”

Section: Mitochondria and Melatoninmentioning

confidence: 99%

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

Tan¹,

Hardeland

2020

Molecules

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Fighting infectious diseases, particularly viral infections, is a demanding task for human health. Targeting the pathogens or targeting the host are different strategies, but with an identical purpose, i.e., to curb the pathogen’s spreading and cure the illness. It appears that targeting a host to increase tolerance against pathogens can be of substantial advantage and is a strategy used in evolution. Practically, it has a broader protective spectrum than that of only targeting the specific pathogens, which differ in terms of susceptibility. Methods for host targeting applied in one pandemic can even be effective for upcoming pandemics with different pathogens. This is even more urgent if we consider the possible concomitance of two respiratory diseases with potential multi-organ afflictions such as Coronavirus disease 2019 (COVID-19) and seasonal flu. Melatonin is a molecule that can enhance the host’s tolerance against pathogen invasions. Due to its antioxidant, anti-inflammatory, and immunoregulatory activities, melatonin has the capacity to reduce the severity and mortality of deadly virus infections including COVID-19. Melatonin is synthesized and functions in mitochondria, which play a critical role in viral infections. Not surprisingly, melatonin synthesis can become a target of viral strategies that manipulate the mitochondrial status. For example, a viral infection can switch energy metabolism from respiration to widely anaerobic glycolysis even if plenty of oxygen is available (the Warburg effect) when the host cell cannot generate acetyl-coenzyme A, a metabolite required for melatonin biosynthesis. Under some conditions, including aging, gender, predisposed health conditions, already compromised mitochondria, when exposed to further viral challenges, lose their capacity for producing sufficient amounts of melatonin. This leads to a reduced support of mitochondrial functions and makes these individuals more vulnerable to infectious diseases. Thus, the maintenance of mitochondrial function by melatonin supplementation can be expected to generate beneficial effects on the outcome of viral infectious diseases, particularly COVID-19.

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Section: Mitochondria and Melatoninmentioning

confidence: 99%

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

Tan¹,

Hardeland

2020

Molecules

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Section: Introductionmentioning

confidence: 99%

“…Melatonin, a neurohormone produced by the pineal gland, 12 has been reported to exert a wide variety of biological activities, such as anti-inflammatory, anti-oxidative, antiapoptotic, and immunomodulatory activities. [13][14][15] Preclinical and clinical studies have shown that melatonin decreases neuroinflammation in PD, 12 but the mechanism underlying this effect remains to be explored. Recent studies on mouse brain injury and major depressive disorder models showed that the anti-inflammatory effect of melatonin was partially attributed to the suppression of NLRP3 inflammasome activity, where melatonin reduced the expression of NLRP3 inflammasome components and the protein levels of IL-1β.…”

Section: Introductionmentioning

confidence: 99%

Melatonin Attenuates Neuroinflammation by Down-Regulating NLRP3 Inflammasome via a SIRT1-Dependent Pathway in MPTP-Induced Models of Parkinson’s Disease

Zheng

Ruan

Yan

et al. 2021

JIR

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Background: Inflammasome-induced neuroinflammation is a key contributor to the pathology of Parkinson's disease (PD). NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation has been implicated in PD in postmortem human PD brains, indicating it as a potential target for PD treatment. Melatonin, a multitasking molecule, has been found to have anti-inflammatory activities, mediated by silence information regulator 1 (SIRT1). However, whether and how melatonin is involved in inflammasome-induced neuroinflammation in PD pathogenesis remains unclear. Methods: We investigated the potential anti-inflammatory effects of melatonin in vitro and in vivo, using 1-methyl-4-phenylpyridinium (MPP + )-simulated BV2 and primary microglia cell models, and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine PD model, with or without melatonin treatment. Rotarod, grip strength, and open-field tests were performed to measure the effects of melatonin on MPTP-induced motor disorders. Degeneration of dopaminergic neurons was evaluated by immunofluorescence. Changes in microglia were examined by immunofluorescence and Western blotting, and the expression levels of the involved signaling molecules were assessed by Western blotting and enzymelinked immunosorbent assay (ELISA). Intracellular reactive oxygen species (ROS) was detected using fluorescent probes via flow cytometry. Results: We found that melatonin significantly alleviated motor dysfunction and prevented MPTP-induced neurotoxicity in dopaminergic neurons. Additionally, melatonin reduced MPTP-induced microglial activation and suppressed NLRP3 inflammasome activity, and also inhibited IL-1β secretion. Moreover, in MPP + -primed BV2 cells, melatonin markedly restored the downregulation of SIRT1 and attenuated the activation of the NLRP3 inflammasome. This was reversed by SIRT1 inhibitor treatment. Conclusion:In conclusion, our data demonstrated that melatonin attenuates neuroinflammation by negatively regulating NLRP3 inflammasome activation via a SIRT1-dependent pathway in MPTP-induced PD models. These findings provide novel insights into the mechanism underlying the anti-inflammatory effects of melatonin in PD.

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“…Extensive regions of the nervous system, various neurotransmitters, and protein aggregates other than Lewy bodies are implicated in the pathology of PD [1]. A complex interplay between genetics and environmental factors results in an increase in oxidative stress (OS), as well as inflammation, autophagy, apoptosis, protein aggregation, and changes in the levels of neurotransmitters [2].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Effect of Alpha-Lipoic Acid in 6-Hydroxydopamine Unilateral Intrastriatal Injected Rats

et al. 2020

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The toxin 6-hydroxydopamine (6-OHDA) is a highly oxidizable dopamine (DA) analog that is widely used for reproducing several cell processes identified in Parkinson’s disease (PD). Due to the close similarity of its neurotoxic mechanism to those of DA, it is suitable as a model for testing the effects of potentially neuroprotective drugs. This study aimed to evaluate the effect of alpha-lipoic acid (LA) on brain oxidative stress (OS) in unilateral intrastriatal (6-OHDA) injected rats. Forty male Wistar rats, four months old (220–260 g), were evaluated. Half of them received LA (35 mg/kg i.p.) from the start to the end of the experiment. On day 2 of the trial, ten LA-supplemented rats and ten non-LA-supplemented rats were subjected to the apomorphine test. Brain homogenates were evaluated for thiobarbituric acid-reactive substances (TBARS) and glutathione peroxidase (GPx) activity. The same evaluation procedures were repeated on day 14 with the remaining animals. An increased TBARS level and decreased GPx activity, suggestive for OS, were recorded in homogenates on day 14 vs. day 2 of the experiment in the 6-OHDA treated rats. The simultaneous application of LA mitigated these changes. Our study demonstrates that the low dose of LA could be of value for decreasing the OS of the neurotoxic 6-OHDA, supporting the need for further studies of the benefit of LA treatment in PD.

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Melatonin and Parkinson Disease: Current Status and Future Perspectives for Molecular Mechanisms

Cited by 50 publications

References 128 publications

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

Melatonin Attenuates Neuroinflammation by Down-Regulating NLRP3 Inflammasome via a SIRT1-Dependent Pathway in MPTP-Induced Models of Parkinson’s Disease

Antioxidant Effect of Alpha-Lipoic Acid in 6-Hydroxydopamine Unilateral Intrastriatal Injected Rats

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