Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Parkinson's disease (PD) is a common neurodegenerative disorder involving multiple pathological processes. Bergapten (BeG) exhibits various pharmacological activities, including anti-inflammatory, antioxidant, and neuroprotective effects, but its mechanism of action in PD remains unclear. Objective: This study aimed to investigate the neuroprotective effects and underlying mechanisms of BeG in PD models. Method: An in vitro neuroinflammation model was established using LPS-treated astrocytes. Results: In-vitro studies demonstrated that BeG counteracted LPS-induced astrocyte activation by reducing the expressions of GFAP, inflammatory mediators (IL-6, TNF-?, IL-1?), and A1 polarization markers. It alleviated ERS (as indicated by reduced levels of GRP78, CHOP) and apoptosis (as shown by changes in Bax, caspase-3) while enhancing Bcl-2. Mechanistically, BeG suppressed LCN2 expression and JAK2/STAT3 phosphorylation, with LCN2 overexpression attenuating its protective effects. In MPTP-treated mice, BeG improved motor function, preserved dopaminergic neurons, and reduced astrocyte activation and A1 polarization. It increased neurotrophic factors (BDNF, GDNF) while decreasing inflammation, ER stress and apoptotic markers. The inhibition of the LCN2/JAK2/STAT3 pathway was consistently observed in both models, suggesting its central role in BeG's neuroprotective mechanism. Conclusion: These findings suggest that BeG exerts neuroprotective effects in PD by inhibiting the LCN2/JAK2/STAT3 signaling pathway, thereby effectively inhibiting astrocyte activation-mediated neuroinflammation and ERS.