Chlorogenic Acid Fails to Confer Neuroprotection in a Chronic Mouse Model of Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein (α-Syn) aggregation, dopaminergic neuronal loss, and chronic neuroinflammation. Chlorogenic acid (CA), a dietary polyphenol abundant in coffee, exhibits antioxidant and anti-inflammatory properties and has shown neuroprotective effects in acute toxin-based PD models. However, its efficacy in chronic, α-Syn-driven PD models remains unclear. Here, we evaluated the therapeutic potential of CA using an α-Syn-based in vitro system and a chronic α-Syn overexpression mouse model that recapitulates key pathological features of human PD. In vitro, CA significantly improved cell viability, reduced α-Syn aggregation, and attenuated H₂O₂-induced apoptosis in U118 and N2a cells. In contrast, chronic oral administration of CA (100 mg/kg for 16 weeks) in C57BL/6 J mice (male and female) failed to improve motor behavior, attenuate α-Syn pathology, preserve nigrostriatal dopaminergic neurons, or reduce oxidative stress-associated DNA double-strand breaks in vivo. Notably, CA elicited a modest reduction in microglial and astrocytic activation in female mice, highlighting a sex-dependent immunomodulatory response. Collectively, these findings reveal a clear dissociation between robust in vitro neuroprotection and limited in vivo efficacy in a chronic α-Syn-driven PD mouse model, emphasizing the importance of incorporating progressive disease paradigms and sex as a biological variable in preclinical therapeutic evaluation.