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 H ₂ O ₂ -induced apoptosis in U118 and N2a cells. In contrast, chronic oral administration of CA (100 mg/kg for 16 weeks) in C57BL/6J 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.