Protective Effects Of Phellodendrine On Cerebral Ischemia Reperfusion Injury

Ischemic stroke is an acute predominant cerebrovascular disease causing brain tissue damage due to blockage of brain blood vessels,thus preventing blood flow into the brain.Timely thrombolytic therapy is the most effective treatment strategy for ischemic stroke,but complex pathophysiological changes occurred byrestoration of blood flow,leading to ischemia-reperfusion(I/R)injury more severe than pure ischemia itself.Phellodendrine,a isoquinoline alkaloid,is one of the most characteristic components and important active ingredients of the Chinese herbal medicine Phellodendri Chinensis cortex(Huangbo).Phellodendrine showed significant biological activities including anti-inflammatory,anti-tumor,anti-oxidative stress and immunosuppressive activity.Use of phellodendrine in the treatment of ischemic stroke has not been reported.In this thesis,MCAO-modeled rats was used to simulate cerebral ischemia-reperfusion injury,and then phellodendrine was administered intraperitoneally at 5 mg/kg during the reperfusion period.Phellodendrine could significantly alleviate ischemic reperfusion injury by reducing neurological dysfunction,cerebral infarction and cerebral edema,and futher reducing the level of oxidative stress.To explore possible mechanism underlying the treatment of cerebral ischemia-reperfusion injury by phellodendrine,LC-MS-based metabolomics stufy on human umbilical vein endothelial cells(HUVECs)from oxygen glucose deprivation reperfusion(OGD/R)was performd,and revealed the implication of oxidative phosphorylation,apoptosis,inflammatory response and other pathways.Based on the metabolic pathways obtained from enrichment analysis of differential metabolites,the protective mechanism of phellodendrine was further investigated.Phollodendrine promoted cell proliferation and migration,maintained intracellular calcium homeostasis and alleviated OGD/Rinduced oxidative stress and apoptosis,and these protective effects were mediated through Akt/Nrf2/HO-1 signaling pathway.The molecular docking results also confirmed the binding of phellodendrine to Akt,which confirmed the metabolomic findings.The above results demonstrated the protective effects of phellodendrine against cerebral ischemia-reperfusion injury and warranted its further development.