Wen Luo1,2, Junqing Yang3. 1. Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China. 2. Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, China. 3. Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China. cqyangjq@cqmu.edu.cn.
Abstract
BACKGROUND: Cerebral ischemia/reperfusion injury (CIRI) has complex pathogenesis, and inhibiting apoptosis and supporting neural progenitor proliferation are extremely beneficial strategies for treating CIRI. Unc-51-like kinase 4 (ULK4), a susceptibility gene for schizophrenia, promotes neural progenitors proliferation. The phosphatidylinositol 3-kinase (PI3K) pathway plays a critical role in CIRI via inhibition of apoptosis. Therefore, the relationship among ULK4, the PI3K pathway, and apoptosis in the context of CIRI has attracted our great interest. METHODS AND RESULTS: Primary cortical neurons were subjected to oxygen-glucose deprivation/reperfusion (OGD/R), and rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). Transfection of the ULK4-overexpression lentivirus was performed alone or in combination with PI3K inhibitor treatment. Here, we revealed that ULK4 was poorly expressed in the cortex in MCAO/R rats and OGD/R-treated primary cortical neurons, ULK4 overexpression inhibited apoptosis, and reduced neurological deficit scores, cerebral infarct volume, and histopathological damage. Moreover, ULK4 overexpression increased PI3K expression and the p-protein kinase B/AKT and p-glycogen synthase kinase 3 beta (GSK3β)/GSK3β ratios, and inhibited apoptosis, while a PI3K inhibitor reversed the effects of ULK4 overexpression on CIRI. CONCLUSIONS: ULK4 protects against CIRI, and the underlying mechanism involves PI3K pathway activation which in turn inhibits apoptosis.
BACKGROUND: Cerebral ischemia/reperfusion injury (CIRI) has complex pathogenesis, and inhibiting apoptosis and supporting neural progenitor proliferation are extremely beneficial strategies for treating CIRI. Unc-51-like kinase 4 (ULK4), a susceptibility gene for schizophrenia, promotes neural progenitors proliferation. The phosphatidylinositol 3-kinase (PI3K) pathway plays a critical role in CIRI via inhibition of apoptosis. Therefore, the relationship among ULK4, the PI3K pathway, and apoptosis in the context of CIRI has attracted our great interest. METHODS AND RESULTS: Primary cortical neurons were subjected to oxygen-glucose deprivation/reperfusion (OGD/R), and rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). Transfection of the ULK4-overexpression lentivirus was performed alone or in combination with PI3K inhibitor treatment. Here, we revealed that ULK4 was poorly expressed in the cortex in MCAO/R rats and OGD/R-treated primary cortical neurons, ULK4 overexpression inhibited apoptosis, and reduced neurological deficit scores, cerebral infarct volume, and histopathological damage. Moreover, ULK4 overexpression increased PI3K expression and the p-protein kinase B/AKT and p-glycogen synthase kinase 3 beta (GSK3β)/GSK3β ratios, and inhibited apoptosis, while a PI3K inhibitor reversed the effects of ULK4 overexpression on CIRI. CONCLUSIONS: ULK4 protects against CIRI, and the underlying mechanism involves PI3K pathway activation which in turn inhibits apoptosis.
Authors: Andrew M Slupe; Ronald A Merrill; Kyle H Flippo; Mark A Lobas; Jon C D Houtman; Stefan Strack Journal: J Biol Chem Date: 2013-03-13 Impact factor: 5.157