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.