Agomelatine Targets Aquaporin-4 Polarization to Rescue Glymphatic Dysfunction in Parkinson's Disease

Melatonin deficiency in Parkinson's disease (PD) patients correlates with impaired glymphatic function as measured by diffusion tensor imaging along the perivascular space (DTI-ALPS) index, suggesting circadian-regulated waste clearance as a therapeutic target. Unlike previous studies focusing on agomelatine's (AGM) antidepressant and sleep-regulating properties, we demonstrate its novel mechanism in PD treatment through glymphatic enhancement. Retrospective clinical analysis of PD patients revealed that AGM administration restored glymphatic function and improved motor performance. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced (MPTP) PD models, AGM alleviated glymphatic dysfunction and anxiety-like behaviors while reducing PD pathology. Crucially, AGM promoted aquaporin-4 (AQP4) polarization at astrocytic endfeet, as evidenced by RNA sequencing showing enhanced gap junction-related gene expression. The brain and muscle ARNT-like 1 (BMAL1)-mediated transcriptional regulation emerged as the key pathway underlying these effects. Our findings establish AGM as the first melatoninergic agent targeting the glymphatic-AQP4 axis in PD, shifting therapeutic strategies from symptomatic relief to disease modification. This provides clinical rationale for repurposing circadian regulators to decelerate PD progression through enhanced protein clearance.