Z-ligustilide activates the Nrf2/HO-1 pathway and protects against cerebral ischemia–reperfusion injury in vivo and in vitro

Abstract

Z-ligustilide (LIG), the main lipophilic component of Radix Angelica sinensis, has been shown to protect against brain ischemic damage in rodents by oral and intra-peritoneal treatments. The present study aimed to confirm the therapeutic effect of LIG administered intravenously on 2h middle cerebral artery occlusion (MCAO) and 22h reperfusion injury in rats since oral administration has low bioavailability, slow absorption and distribution. Moreover, whether LIG activated the NF-E2-related factor 2/ heme oxygenase-1 (Nrf2/HO-1) pathway was also investigated in vivo and in vitro to further elucidate the precise protective mechanisms. In vivo, rats treated intravenously with LIG immediately after the surgery was finished had less neurological dysfunction and smaller infarct volume than that of the vehicle-treated rats. Additionally, LIG promoted Nrf2 nuclear translocation, and further remarkably increased Nrf2 and HO-1 protein expression. In vitro, LIG induced Nrf2 nuclear translocation and up-regulated HO-1 expression in a time-dependent and concentration-dependent manner. Furthermore, LIG treatment reduced cell death induced by OGD, however, the protective action was abolished while Nrf2/HO-1 expression was knockdown by RNA interference. These results noted that intravenous post-treatment with LIG exhibits noticeable neuroprotective properties against brain damage by ischemia–reperfusion and the ability of LIG to activate Nrf2/HO-1 pathway may be partly responsible for it.