Cilostazol novel neuroprotective mechanism against rotenone-induced Parkinson's disease in rats: Correlation between Nrf2 and HMGB1/TLR4/PI3K/Akt/mTOR signaling.

Abstract

This study investigated the novel neuroprotective effect of cilostazol on rotenone-intoxicated rats focusing on the HMGB1/TLR4 axis, erythroid-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1), and phosphoinositide 3-kinase (PI3K)/Protein kinase B (Akt)/the mammalian target of rapamycin (mTOR) pathway. The aim is extended to correlate the Nrf2 expression with all assessed parameters as promising therapeutic targets for neuroprotection. Our experiment was designed as follows: vehicle group, cilostazol group, rotenone group (1.5mg/kg, s.c), and the rotenone pretreated with cilostazol (50mg/kg, p.o.) group. Eleven rotenone injections were injected day after day, while cilostazol was administered daily for 21days. Cilostazol significantly improved the neurobehavioral analysis, the histopathological examination, and dopamine levels. Moreover, the immunoreactivity of tyrosine hydroxylase (TH) in substantia nigra pars compacta (SNpc) enhanced. These effects were associated with enhancement of the antioxidant expression of Nrf2 and HO-1 by 1.01 and 1.08-fold, respectively, and repression of HMGB1/TLR4 pathway by 50.2% and 39.3%, respectively. Upregulation of the neuro-survival PI3K and Akt expression by 2.26 and 2.69-fold, respectively, and readjusting mTOR overexpression. Cilostazol exerts a novel neuroprotective strategy against rotenone-induced neurodegeneration via activation of Nrf2/HO-1, suppression of HMGB1/TLR4 axis, upregulation of PI3K/Akt besides mTOR inhibition that compels more investigations with different PD models to clarify its precise role.