The Research Of Autophagy After Global Cerebral Ischemia And Novel Brain Protection Strategies

OBJECT: Global cerebral ischemia-reperfusion can lead to neuronal apoptosis and neurological damage,which can usually occur under cardiac arrest,shock,extracorporeal circulation,traumatic hemorrhage,and asphyxia.And autophagy plays an important role in this process.This article aims to establish two models of global cerebral ischemia-reperfusion and use drugs to treat cerebral neuronal injury,and to explore the underlying mechanism.METHODS:(1)The transient global cerebral ischemia model(t GCI)was established by double-common carotid artery occlusion combined with hypotension,and after b FGF(basic fibroblast growth factor)was administered,molecular biology and behavioral methods were employed to detect whether brain damage was attenuated,and further explore the mechanism;(2)Established a model of asphyxia cardiac arrestcardiopulmonary resuscitation(CA-ROSC)model to simulate clinical cardiac arrest,and prepared the HIF-2a inhibitor 2ME2 into ANG-PEG-2ME2 / 2ME2 nanomicelles,which is targeted for the penetration of the blood-brain barrier(BBB).Then we evaluated the absorption of drugs in the brain,detected apoptosis-related proteins and analyzed the degree of brain injury improvement by histochemistry.Eventually we evaluated the neurological deficit scores;(3)Detected the integrity of autophagic flux after CA-ROSC by molecular biology methods and observed the changes of lysosomal protein and autophagy flow after inhibition of ROS.RESULTS:(1)After t GCI assault,autophagy could be activated through the m TOR pathway,and apoptosis was induced in the hippocampal CA1 region via p53 mitochondrial translocation.Excessive autophagy will lead to further brain damage,and i.c.v.injection of b FGF could inhibit excessive autophagy and cell apoptosis.b FGF played a neuroprotective role and improve memory function in this process;(2)ANG-PEG-2ME2/2ME2 micelles can successfully penetrated the blood-brain barrier to reach the damaged brain area,and reduced the occurrence of apoptosis in the damaged area after CA-ROSC.It could also increased the number of viable neurons,and ultimately improve the scores of neurological deficit;(3)After CAROSC,the expression of lysosome-related proteins decreased,and autophagic flux was impaired,while inhibition of excessively produced ROS could improve the degree of lysosomal damage,thereby reduced the degree of impaired autophagy.CONCLUSION: Through the establishment of global cerebral ischemiareperfusion models such as t GCI and CA-ROSC,the relevant role of autophagy in brain injury after ischemia-reperfusion was studied;b FGF can inhibit the excessive autophagy and apoptosis in the brain after global ischemia-reperfusion.It plays a protective role during this process;ANGPEG-2ME2/2ME2 could efficiently penetrate the blood-brain barrier and spread to the injured brain area,which is superior to free 2ME2,and has neuroprotective effect on cerebral ischemia-reperfusion injury after CAROSC;And we explored the mechanism of impaired autophagic flux after CA-ROSC.To sum up,this series of researches provide a new idea and strategy for clinical global cerebral ischemia-reperfusion injury.