An important pathophysiological component of Parkinson’s Disease (PD) is circadian rhythm disorder, closely related to a decrease in circulated melatonin (MLT) level. It has been reported recently that retinoic acid-associated orphan nuclear receptor (RORα), for the potentiallyendogenous ligand MLT, plays an important role in various diseases. However, the function of RORα in the pathogenesis of neurodegenerative diseases remains much unclear. Here, we showed in a cellular PD model that RORα expression was down-regulated in 1 methyl 4 phenyl pyridinium ion (MPP+)-treated BV2 cells but up-regulated by MLT. Of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - induced mouse model with RORα levels reduced in the midbrain tissue, MLT treatment (intraperitoneal 20 mg/kg/d for 7 days) significantly increased the RORα levels and protected dopamine neurons, with decreased inflammation and increased anti-inflammatory M2-like phenotype in the microglia. Furthermore, siRNA-mediated knockdown implied the involvement of signal transducer and activator of transcription (STAT) pathway. In conclusion, MLT ameliorates neuroinflammation by inhibiting STAT-related pro-inflammatory (M1-like) polarization of microglia, revealing alternative options for neuroprotective treatment of PD.

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Parkinson’s disease (PD) is a complex, multisystem disorder with both neurologic and systemic manifestations, which is usually associated with non-motor symptoms, including sleep disorders. Such associated sleep disorders are commonly observed as REM sleep behavior disorder, insomnia, sleep-related breathing disorders, excessive daytime sleepiness, restless legs syndrome and periodic limb movements. Melatonin has a wide range of regulatory effects, such as synchronizing circadian rhythm, and is expected to be a potential new circadian treatment of sleep disorders in PD patients. In fact, ongoing clinical trials with melatonin in PD highlight melatonin’s therapeutic effects in this disease. Mechanistically, melatonin plays its antioxidant, anti-inflammatory, anti-excitotoxity, anti-synaptic dysfunction and anti-apoptotic activities. In addition, melatonin attenuates the effects of genetic variation in the clock genes of Baml1 and Per1 to restore the circadian rhythm. Together, melatonin exerts various therapeutic effects in PD but their specific mechanisms require further investigations.