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.

Figure 1

Summary of molecular mechanisms associated with neuroprotective effects of melatonin in in vivo and in vitro models of Parkinson's disease. The main molecular mechanism of neurotoxins is related to its ability to inhibit the complexes of the mitochondrial electron transport chain. The inhibition of these complexes leads to an increased production of reactive oxygen species (ROS) and, consequently, to mitochondrial dysfunction, oxidative stress, activation of apoptotic pathways, and neuroinflammation, culminating in neuronal cell death. Melatonin exerts neuroprotective effects through different mechanisms: protection of the complex I activity, neutralization of ROS, increased cell antioxidant defences, reducing neuroinflammation, inhibition of caspases cascade, and cellular apoptosis. Melatonin is also able to protect against induction of Bax and Cdk5/p35 expression and inhibition of Parkin/PINK1 and Bcl-2 expression induced by toxins in PD models. 6-OHDA: 6-hydroxydopamine; Bak: Bcl2 antagonist/killer; Bax: Bcl2 associated X; Bcl2: B cell leukemia/lymphoma 2; Cdk5: cyclin-dependent kinase 5; Cyt C: Cytochrome C; IAPs: inhibitors of apoptosis proteins; MPP⁺: 1-methyl-4-phenylpyridinium; Omi/HtrA2: HtrA serine peptidase 2; ROS: reactive oxygen species.