Naftidrofuryl Exerts Neuroprotective Effects in a Rotenone-Induced Rat Model of Parkinson's Disease Through Modulation of PINK1/Parkin and ER Stress Pathways.

Background: Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration associated with oxidative stress, dysregulated endoplasmic reticulum (ER) stress, impaired mitophagy, and neuroinflammation. Although rotenone (ROT) reliably induces these pathological features, there remains a lack of effective pharmacological agents capable of simultaneously modulating ER-stress and PINK1/Parkin-dependent mitophagy representing an important gap in current PD research. Objective: This study aimed to investigate whether naftidrofuryl (NFD), a vasoactive and cytoprotective agent, can attenuate ROT-induced neurobehavioral, biochemical, and molecular alterations through modulation of ER-stress signaling and PINK1/Parkin-mediated mitophagy. Methods: Forty male Wistar rats were assigned to four groups (Control, NFD, ROT, ROT + NFD combination). Behavioral assessments (Y-maze, rotarod, tail suspension), oxidative/antioxidant biomarkers, inflammatory cytokines, dopamine levels, ER-stress markers (BIP, ATF6, eIF2α/CHOP), mitophagy mediators (PINK1, Parkin), SNCA expression, miR-124 expression, histopathology, and caspase-1 immunoreactivity were evaluated. Results: ROT administration induced marked cognitive and motor impairment, elevated oxidative and nitrosative stress, increased pro-inflammatory cytokines, reduced antioxidant capacity, and upregulated ER-stress mediators. ROT also downregulated PINK1/Parkin expression suppressed miR-124, elevated SNCA, and produced significant neuronal degeneration with increased caspase-1 activation. NFD treatment significantly ameliorated these alterations by reducing oxidative stress and inflammatory cytokines, restoring antioxidant markers, attenuating ER-stress activation, enhancing PINK1/Parkin-dependent mitophagy, normalizing miR-124 expression, reducing SNCA expression, and improving histopathological and behavioral outcomes. Conclusion: NFD demonstrated robust neuroprotective effects against ROT-induced neurotoxicity, likely through coordinated modulation of ER-stress pathways, restoration of PINK1/Parkin signaling, reduction of oxidative and inflammatory responses, and preservation of neuronal integrity. These findings suggest a potential mechanistic role for NFD in mitigating early PD-related neurodegenerative changes, warranting further preclinical investigation.