Aesculus hippocastanum Extract Exerts Neuroprotective Effects in an MPP + ‐Induced Parkinson's Disease Model via PPARγ Activation

ABSTRACT Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. In this study, we investigated the neuroprotective and anti‐inflammatory potential of Aesculus hippocastanum (horse chestnut extract, HCE) in an in vitro model of PD. Human neuroblastoma SH‐SY5Y cells were treated with the neurotoxin 1‐methyl‐4‐phenylpyridinium (MPP + ) (1 mM) and/or in combination with HCE at the concentrations of 15.6, 31.2 and 62.5 μg/mL for 24 h. After 24 h, several analyses have been performed. Treatment with HCE at the concentrations of 31.2 and 62.5 μg/mL significantly improved cell viability following MPP + ‐induced neurotoxicity. Furthermore, HCE effectively modulated key Parkinsonian markers by restoring tyrosine hydroxylase (TH) and reducing the number of α‐syn‐positive cells. At the same concentrations, HCE also attenuated NF‐κB signalling pathway activation and diminished the release of pro‐inflammatory cytokines IL‐1β, IL‐17, and TNF‐α. Notably, HCE promoted the activation of the nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ), known for its neuroprotective properties, and reduced both oxidative and nitrosative stress. Crucially, silencing of PPARγ abolished the beneficial effects of HCE, indicating that its neuroprotective actions are mediated specifically through PPARγ activation. Thus, these findings suggest that HCE confers neuroprotection in vitro by regulating inflammation and oxidative stress primarily via PPARγ modulation.