Dual targeting of melatonergic and serotonergic neurotransmissions in Parkinson's disease: role of agomelatine.

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder of the central nervous system (CNS), driven by the pathological aggregation and accumulation of α-synuclein (α-Syn) within dopaminergic neurons of the substantia nigra pars compacta (SNpc). Despite extensive research, the pathogenesis of PD remains incompletely understood and involves complex molecular signaling pathways. Melatonin and serotonin are dysregulated in PD and may contribute to cognitive impairment, sleep disturbances, and neuropsychiatric manifestations. Accordingly, restoration of melatonergic and serotonergic neurotransmission may support the management of depressive symptoms, cognitive impairment, and sleep disorders in patients with PD. Agomelatine, used in the management of major depressive disorder, can modulate both melatonergic and serotonergic neurotransmission. However, its molecular mechanisms and potential effects on the development and progression of PD have not been comprehensively evaluated. A literature search was conducted using PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar from database inception to July 2026, using relevant keywords and MeSH terms related to PD, melatonergic and serotonergic neurotransmission, and agomelatine. Therefore, this narrative review discusses the role of melatonergic and serotonergic neurotransmission in PD and examines how targeting these pathways with agomelatine may contribute to PD management.