Role of PI3K/mTOR/autophagy Pathway in Global Cerebral Ischemia/reperfusion Injury Aggravated by Intermittent Hypoxia in Rats / 中国医科大学学报

ABSTRACT

Objective To investigate the changes in the expression of phosphatidylinositol 3?kinase(PI3?K),mammalian target of rapamycin (mTOR)and Beclin?1 in the hippocampus of normal rats and intermittent hypoxia rats with cerebral ischemia/reperfusion ,so as to explore the role of PI3K/mTOR/autophagy pathway in global cerebral ischemia/reperfusion injury aggravated by intermittent hypoxia. Methods A total of 80 healthy male Wistar rats were randomly divided into sham operation group(SO group,n=20),merely ischemia/reperfusion group(I/R group,n=20),intermittent hypoxia for 7?day ischemia/reperfusion group(IH7+I/R group,n=20),and intermittent hypoxia for 21?day ischemia/reperfusion group(IH21+I/R group,n=20). IH7+I/R group and IH21+I/R group were respectively given intermittent hypoxia for 7 days and 21 days before ischemia/reperfusion. The cerebral ischemia/reperfusion model was established by modified Pulsinelli four?vessel occlusion method. The morpholog?ical changes of nerve cells in hippocampal CA1 region were observed by HE staining and electron microscope. The protein expressions of PI3?K, mTOR and Beclin?1 of nerve cells in hippocampal CA1 region were detected by immunohistochemical staining and RT?PCR. The learning memory capacity of rats were assessed by the Morris water maze test. Results Compared with SO group,I/R group increased the never cells morphology damages,reduced the number of survival neurons,and declined the ability of learning and memory(P<0.05). Immunohistochemistry showed that the number of PI3?K immunoreactive cell,mTOR immunoreactive cell and Beclin?1 immunoreactive cell increased in I/R group compared with S0 group(P<0.05). RT?PCR showed that the expressions of PI3?K,mTOR and Beclin?1 increased in I/R group compared with S0 group(P<0.05). Compared with I/R group,intermittent hypoxia groups increased the never cells morphology damages,decreased the number of survival neu?rons,and declined the ability of learning and memory(P<0.05). Immunohistochemistry showed that the number of PI3?K immunoreactive cell, mTOR immunoreactive cell and Beclin?1 immunoreactive cell increased in IH7+I/R and IH21+I/R groups compared with I/R group(P<0.05). RT?PCR showed that the expressions of PI3?K,mTOR and Beclin?1 increased in IH7+I/R and IH21+I/R groups compared with I/R group(P<0.05),and the changes were more significant in IH21+I/R group(P<0.05). Conclusion Intermittent hypoxia can aggravate neurological injury after ischemia,which is related to PI3K/mTOR/autophagy pathway activation.