O receptor P2X7 microglial orquestra neuroinflamação, disfunção autofágica e sinucleinopatia em ratos parkinsonianos

Abstract

Parkinson’s disease (PD) is a multisystem neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the presence of protein inclusions known as Lewy bodies, which are primarily composed of aggregated α-synuclein. Under physiological conditions, these proteins are targeted for autophagic degradation. Hyperactivity of purinergic P2X7 receptors has been extensively implicated in the pathophysiology of PD, with growing evidence supporting their role in autophagic dysfunction and protein aggregation. Thus, the present study aimed to investigate the neuroprotective effect of the P2X7 receptor antagonist Brilliant Blue G (BBG), administered during a prodromal phase of PD, focusing on its impact on α-synuclein accumulation and dysfunction of autophagic pathways in an experimental model of rotenone-induced parkinsonism. For this purpose, male Wistar rats were divided into four groups: control, control treated, parkinsonian (rotenone 2.75 mg/kg for 21 days, intraperitoneally), and parkinsonian treated with BBG (50 mg/kg for 15 days, intraperitoneally). Animals were subjected to behavioral tests and, at the end of the protocol, euthanized for brain collection for immunohistochemical and molecular analyses. P2X7 receptor blockade significantly protected the animals against deficits in volatile odor detection, locomotor activity (open field test), motor coordination (rotarod test), depressive-like behavior (sucrose preference test), and working memory (Y-maze test) induced by rotenone exposure. BBG prevented the loss of dopaminergic neurons in the substantia nigra and striatum,

reduced neuroinflammation, and decreased the accumulation of total and phosphorylated α- synuclein. Additionally, BBG modulated autophagic and mitophagic pathways, as evidenced

by reduced expression of proteins such as LC3 and PINK1. The effect of BBG occurred by decreasing the number of microglial P2X7 receptors. The results indicate that rotenone-induced microglial purinergic hyperactivity acts as a multifaceted pathogenic integration center, amplifying neuroinflammation, disrupting autophagic processes, and promoting the accumulation of pathogenic α-synuclein, thereby creating a vicious cycle that culminates in dopaminergic neuronal death. Thus, P2X7 receptor blockade emerges as a promising therapeutic approach for targeting multiple pathological pathways in PD.