The protective effect of febuxostat in a rotenone mouse model of Parkinson's disease: the interplay between PI3K/Akt/mTOR, GSK-3β, and Nrf2/HO-1 signaling pathways.

OBJECTIVES: In a rotenone-induced Parkinson's disease (PD) mouse model, our study explored the neuroprotective effect of febuxostat, a non-purine selective xanthine oxidase inhibitor approved for gout management. In addition, this study explored the role of PI3K/Akt signaling and its downstream effectors in this neuroprotective activity.

METHODS: Mice were administered rotenone (1.5 mg/kg, s.c., every 48 h) for 3 weeks to induce PD. Mice were treated with febuxostat (5 mg/kg, p.o.) daily 1 h before rotenone.

KEY FINDINGS: Febuxostat improved motor function in open field, rotarod, and grip strength tests, attenuated body weight loss, preserved dopaminergic neurons, and restored TH levels in the striatum and substantia nigra (SN), elevated PI3K, p-Akt, and p-mTOR, increased the expression of Nrf2, lowered the expression of p-GSK-3β (Tyr216) and Bax/Bcl2 ratio, replenished GSH and HO-1 levels, and reduced MDA, TNF-α, and NF-κB levels in the striatum of rotenone-intoxicated mice.

CONCLUSIONS: This study revealed that febuxostat provides neuroprotective benefits in a rotenone-induced PD model in mice. These beneficial effects are likely due to inhibition of oxidative stress, inflammation, and apoptosis. Additionally, the observed antioxidant, anti-inflammatory, and anti-apoptotic effects of febuxostat may be related to its ability to activate PI3K/Akt/mTOR cascade, diminish p-GSK-3β expression, and up-regulate Nrf2/HO-1 signaling.