Beneficial consequences of Lupeol on middle cerebral artery-induced cerebral ischemia in the rat involves Nrf2 and P38 MAPK modulation

Lupeol has been reported to exhibit anti-inflammatory and anti-tumor activities in many diseases, but its potential effects in cerebral ischemia injury have not been studied to date. In this work we present evidence for a beneficial effect of lupeol in a rat model of middle cerebral artery occlusion (MCAO) followed by reperfusion (MCAO/R) injury and provide some histological and biochemical evidence for its mechanism of action. A cerebral MCAO rat model was established by vascular occlusion for 2 h, followed by 24 h reperfusion period. The infarct volume, neurological deficits, and brain water content were compared with animals treated during reperfusion with different concentrations of lupeol. Macroscopic parameters, cell viability, pro-inflammatory factors generation, as well as oxidative stress parameters and associated apoptotic signaling cascades were evaluated. Treatment with lupeol significantly reduced the cerebral infarct volume and water content and recovered neuro behavioral functions in affected rats. Lupeol treatment down-regulated the expression of oxidative stress and inflammation factors. In addition, lupeol activated Nrf2, suppressed caspase-3 activity, reduced BAX/Bcl-2 ratio and inhibited phosphorylation of p38 MAPK. The data suggest that lupeol may exert protective effects against cerebral ischemia by suppressing oxidative stress and reduction of inflammation factors possible via activation of nuclear transcription factors and inhibition of cell death pathways.