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bioRxiv · 10.64898/2026.04.19.719432

Chlorogenic acid fails to confer neuroprotection in a chronic mouse model of Parkinsons disease

Rajan, A.·Prakash, S.·Singh, D.·Thakur, P.
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Abstract

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by -Synuclein (-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, -Syn-driven PD models remains unclear. Here, we evaluated the therapeutic potential of CA using an -Syn-based in vitro system and a chronic -Syn overexpression mouse model that recapitulates key pathological features of human PD. In vitro, CA significantly improved cell viability, reduced -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/6J mice (male and female) failed to improve motor behavior, attenuate -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 -Syn-driven PD mouse model, emphasizing the importance of incorporating progressive disease paradigms and sex as a biological variable in preclinical therapeutic evaluation.

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Rajan, A., Prakash, S., Singh, D., Thakur, P.. 2026-04-22. Chlorogenic acid fails to confer neuroprotection in a chronic mouse model of Parkinsons disease. https://doi.org/10.64898/2026.04.19.719432

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