Neohesperidin attenuates cerebral ischemia-reperfusion injury via inhibiting the apoptotic pathway and activating the Akt/Nrf2/HO-1 pathway.

Oxidative stress is well known to play a pivotal role in cerebral ischemia-reperfusion injury. On the basis of this fact, antioxidative agents have been demonstrated to be neuroprotective. Neohesperidin (NH) is abundant in citrus flavonoids and possesses reactive oxygen species scavenging activity and neuroprotective effects in vitro. However, little is known about its effects on cerebral ischemia-reperfusion injury and the underlying mechanisms. In this study, we use a rat model of middle cerebral artery occlusion (MCAO) to investigate the neuroprotective effects of NH. NH significantly improved neurological functions and attenuated MCAO-induced infarct volume, pathological changes, and neuronal loss. Moreover, it enhanced antioxidant capacity and suppressed oxidative stress in the brain. NH inhibited the MCAO-induced upregulation of Bax, cytochrome c, and cleaved caspase-9 and -3, as well as the downregulation of Bcl-2. Interestingly, NH treatment upregulated heme oxygenase-1 (HO-1) in a concentration-dependent manner, which was due to the NH-mediated activation of the protein kinase B (Akt)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. NH also abolished the MCAO-induced inhibition of the Akt/Nrf2 pathway. In conclusion, NH attenuates cerebral ischemia-reperfusion injury via the inhibition of neuronal apoptosis and oxidative stress through the regulation of the apoptotic pathway and the Akt/Nrf2/HO-1 pathway. NH might be a promising preventive agent for ischemic stroke.