Vishwa Shah

 Background: Parkinson’s Disease (PD) is a progressive movement disorder caused by neurodegenerative loss of dopaminergic motor neurons in the substantia nigra.¹ Alongside motor symptoms, PD patients also present with non-motor symptoms such as masked facies, hormonal dysregulation, and sleep disturbances that are associated with circadian rhythms.¹ The body’s circadian rhythms are regulated every twenty-four hours by the hypothalamic suprachiasmatic nucleus. A core set of clock genes (BMAL1, CLOCK, CRY1, PER1, and PER2) interact via a transcriptional-translational negative feedback loop to generate and maintain circadian rhythms.² In addition to regulating the sleep/wake cycle, the circadian clock coordinates the timing of melatonin secretion. Melatonin is a neuroendocrine hormone rhythmically secreted from the pineal gland that serves as a time-of-day marker for circadian rhythm levels.³ Transmembrane melatonin receptors can promote downstream effects that may impact the progression and/or treatment of neurodegenerative diseases such as Parkinson’s Disease.³ Therefore, melatonin may serve a vital role in the relationship between PD and circadian rhythms.

Objective: In this narrative review, we explored the role of melatonin and how it serves as a mediator between Parkinson’s Disease and circadian rhythms.

Search Methods: An online search in the PubMed database was conducted from 2017-2023 using keywords such as “Parkinson’s”, “circadian rhythms”, “melatonin”, and “neuroprotectant role”.

Results: A study measuring clock gene mRNA expression from peripheral blood mononuclear cells (PBMCs) displayed significantly low levels of all five clock genes in PD patients compared to healthy controls.³ When evaluating plasma melatonin concentrations, results presented a significant decrease in melatonin levels in PD patients which were constitutively lower at different time periods compared to healthy controls.³ Moreover, a clinical study analyzing the clock genes of PD patients found that BMAL1 levels increased (0.56 to 2.5) after 25mg of melatonin administration whereas PER1 levels remained constant.⁴ Fewer patients reported sleep disturbances suggesting improved sleep quality after melatonin intervention.⁴ Similarly, to highlight the additional role of melatonin as a neuroprotectant, a study looked at a model of neurodegeneration in rodents who were exposed to continuous light exposure (CLE).⁵ CLE promoted a constant state of inflammation by elevating TNF-a, an inflammatory marker that is elevated in PD.^5,6 Supplementation with 10mg of melatonin alleviated the elevation of TNF-a suggesting melatonin as a means of reducing neuroinflammation in PD patients.⁵

Conclusion: Studies have found that melatonin levels and circadian clock genes are depressed in PD patients. However, melatonin supplementation served to increase clock gene levels and alleviate high TNF-a levels in PD patients.  Taken together, melatonin may serve a dual role in reducing PD neuroinflammation and alleviating sleep-wake disturbances observed among PD patients. Areas of ongoing research are elucidating how melatonin serves a neuroprotective role in PD by protecting against age-related brain mitochondrial dysregulation as well as how melatonin secretion may be both a contributor to and result of PD progression.⁷ Through advances in these current research areas, the role of melatonin in the pathogenesis and treatment of PD may be further disclosed.

Works Cited:

1. Li H, Song S, Wang Y, et al. Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats [published correction appears in Neurotox Res. 2018 Nov 21;:]. Neurotox Res. 2019;35(2):421-431. doi:10.1007/s12640-018-9968-1
2. Li SY, Wang YL, Liu WW, et al. Long-term Levodopa Treatment Accelerates the Circadian Rhythm Dysfunction in a 6-hydroxydopamine Rat Model of Parkinson’s Disease. Chin Med J (Engl). 2017;130(9):1085-1092. doi:10.4103/0366-6999.204920
3. Li T, Cheng C, Jia C, et al. Peripheral Clock System Abnormalities in Patients With Parkinson’s Disease. Front Aging Neurosci. 2021;13:736026. Published 2021 Oct 1. doi:10.3389/fnagi.2021.736026
4. Delgado-Lara DL, González-Enríquez GV, Torres-Mendoza BM, et al. Effect of melatonin administration on the PER1 and BMAL1 clock genes in patients with Parkinson’s disease. Biomed Pharmacother. 2020;129:110485. doi:10.1016/j.biopha.2020.110485
5. Verma AK, Singh S, Garg G, Rizvi SI. Melatonin exerts neuroprotection in a chronodisrupted rat model through reduction in oxidative stress and modulation of autophagy. Chronobiol Int. 2022;39(1):45-56. doi:10.1080/07420528.2021.1966025
6. Liu TW, Chen CM, Chang KH. Biomarker of Neuroinflammation in Parkinson’s Disease. Int J Mol Sci. 2022;23(8):4148. Published 2022 Apr 8. doi:10.3390/ijms23084148
7. Li S, Wang Y, Wang F, Hu LF, Liu CF. A New Perspective for Parkinson’s Disease: Circadian Rhythm. Neurosci Bull. 2017;33(1):62-72. doi:10.1007/s12264-016-0089-7