Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms

Abstract

Melatonin is synthesized by several tissues besides the pineal gland, and beyond its regulatory effects in light-dark cycle, melatonin is a hormone with neuroprotective, anti-inflammatory, and antioxidant properties. Melatonin acts as a free-radical scavenger, reducing reactive species and improving mitochondrial homeostasis. Melatonin also regulates the expression of neurotrophins that are involved in the survival of dopaminergic neurons and reduces α-synuclein aggregation, thus protecting the dopaminergic system against damage. The unbalance of pineal melatonin synthesis can predispose the organism to inflammatory and neurodegenerative diseases such as Parkinson's disease (PD). The aim of this review is to summarize the knowledge about the potential role of the melatoninergic system in the pathogenesis and treatment of PD. The literature reviewed here indicates that PD is associated with impaired brain expression of melatonin and its receptors MT1 and MT2. Exogenous melatonin treatment presented an outstanding neuroprotective effect in animal models of PD induced by different toxins, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat, and maneb. Despite the neuroprotective effects and the improvement of motor impairments, melatonin also presents the potential to improve nonmotor symptoms commonly experienced by PD patients such as sleep and anxiety disorders, depression, and memory dysfunction.

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

“…Aside from its classical 2 of 20 action on sleep/wake cycles, melatonin has largely been shown to be a pleiotropic molecule [1][2][3][4] with multiple beneficial actions. In agreement, animal studies have shown melatonin to be an effective neuroprotectant in a number of neurodegenerative conditions such as hypoxia/ischemia [5][6][7], Alzheimer's Disease [8], Parkinson's Disease [9], and spinal cord injury [10]. Notably, clinical trials have been designed to establish the potential neuroprotective efficacy of melatonin in humans [11].…”

Melatonin and inflammation—Story of a double‐edged blade

“…As melatonin can also display proinflammatory properties, for example, in arthritis, caution is due in all autoimmune diseases. In the case of Parkinson's disease (PD), numerous preclinical findings have indicated a beneficial role of melatonin, however, mainly in models based on mitochondrial dysfunction in the nigrostriatum and mostly without considering the early pre‐motor symptoms that reflect the initial stages of the disease. Moreover, several findings have remained contradictory .…”

Twenty Years After: Another Case Report of Melatonin Effects on REM Sleep Behavior Disorder, Using Serial Dopamine Transporter Imaging

“…Neuroprotective effects of melatonin have been reported in the literature at the molecular, cellular, and tissue level in vitro and in animal models (reviewed by Mack et al [14]), to be achieved either by direct cellular scavenger mechanisms [15] or by melatonin receptor-mediated pathways [16]. At present, we have no indication or suggestion which of these or other mechanisms could be responsible for the remarkable improvement of the patient’s condition with melatonin treatment.…”