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

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.