Chicoric acid alleviates rotenone‐induced motor dysfunction in mice: Targeting PI3K/AKT/caspase‐3‐associated apoptosis and neuroinflammation

Abstract Parkinson's disease (PD) is an idiopathic disease characterized by loss of the dopaminergic neurons with inflammatory and apoptotic responses. The phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) axis plays a critical role in promoting neuronal survival. Chicoric acid (CA) is an antioxidant compound that can cross the blood–brain barrier. It has been shown to activate PI3K/AKT and mitigate neuroinflammatory and oxidative damage. Our work aims to examine the neuroprotective effects of CA against rotenone‐induced PD by targeting the PI3K/AKT pathway. Forty male mice were assigned to four groups: (1) control, (2) CA (35 mg/kg/day; p.o.) for 12 days, (3) rotenone (1.5 mg/kg/2 days, i.p.) for 21 days, and (4) combined CA and rotenone administration. The findings revealed that CA improved behavior and histopathological outcomes. These neuroprotective effects were mediated by activating the striatal PI3K/AKT pathway and lowering caspase‐3 levels. Moreover, CA exerted prominent anti‐inflammatory actions by lowering interleukin‐1β (IL‐1β), tumor necrosis factor (TNF)‐α, and nuclear factor kappa B (NF‐κB). A significant increase in antioxidant defenses was evidenced by elevated levels of reduced glutathione (GSH) and superoxide dismutase (SOD) antioxidant mediators. In conclusion, CA showed promising neuroprotective effects in rotenone‐induced PD by activating the PI3K/AKT pathway and inhibiting apoptosis and inflammation.