Blockade of HCN2 Channels Provides Neuroprotection Against Ischemic Injury via Accelerating Autophagic Degradation in Hippocampal Neurons

作     者：Cheng Chen Li Liu Ya-Qiao Shu Ping Jing Yun Lu Xiao-Xue Zhang Xian-Gang Zong Lian-Jun Guo Chang-Jun Li Cheng Chen;Li Liu;Ya-Qiao Shu;Ping Jing;Yun Lu;Xiao-Xue Zhang;Xian-Gang Zong;Lian-Jun Guo;Chang-Jun Li

作者机构：Department of PharmacologySchool of Basic Medical SciencesTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of NeurologyThe Central Hospital of WuhanTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Office of Academic ResearchThe Central Hospital of WuhanTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of PharmacyZhongnan Hospital of Wuhan UniversityWuhan 430030China Department of Clinical LaboratoryWuhan PuAi HospitalWuhan 430033China Key Laboratory of Drug Target Research and Pharmacodynamic EvaluationWuhan 430030China Center for Integrated Protein Science and Zentrum fur PharmaforschungDepartment PharmazieLudwig-Maximilians-Universitat Miinchen80539 MunichGermany 

出 版 物：《Neuroscience Bulletin》 (神经科学通报（英文版）)

年 卷 期：2020年第36卷第8期

页      面：875-894页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100204[医学-神经病学] 10[医学] 

基　　金：supported by grants from the National Natural Science Foundation of China (85100929) the Natural Science Foundation of Hubei Province,China (2018CFB302 and 2019CFB446) the Youth Fund of Health and Family Planning Commission of Wuhan Municipality,Hubei Province,China (WX18Q13 and WX18Q22) 

主　　题：HCN2 channel Autophagy Neuroprotection Oxygen-glucose deprivation/reperfusion Transient global cerebral ischemia 

摘      要：In the central nervous system,hyperpolarizationactivated cyclic nucleotide-gated(HCN)channels are essential to maintain normal neuronal *** studies have shown that HCN channels may be involved in the pathological process of ischemic brain injury,but the mechanisms remain *** is activated in cerebral ischemia,but its role in cell death/survival remains *** this study,our results showed that the HCN channel blocker ZD7288 remarkably decreased the percentage of apoptotic neurons and corrected the excessive autophagy induced by oxygen-glucose deprivation followed by reperfusion(OGD/R)in hippocampal HT22 ***,in the OGD/R group,p-mTOR,p-ULK1(Ser757),and p62 were significantly decreased,while p-ULK1(Ser317),atg5,and beclin1 were remarkably ***7288 did not change the expression of p-ULK1(Ser757),ULK1(Ser317),p62,Beclin1,and atg5,which are involved in regulating autophagosome ***,we found that OGD/R induced a significant increase in Cathepsin D expression,but not *** with ZD7288 at 10μmol/L in the OGD/R group did not change the expression of cathepsin D and ***,chloroquine(CQ),which decreases autophagosome-lysosome fusion,eliminated the correction of excessive autophagy and neuroprotection by ***,shRNA knockdown of HCN2 channels significantly reduced the accumulation of LC3-Ⅱand increased neuron survival in the OGD/R and transient global cerebral ischemia(TGCI)models,and CQ also eliminated the effects of ***,we found that the percentage of LC3-positive puncta that co-localized with LAMP-1-positive lysosomes decreased in Con-shRNAtransfected HT22 neurons exposed to OGD/R or *** HCN2-shRNA-transfected HT22 neurons,the percentage of LC3-positive puncta that co-localized with LAMP-1-positive lysosomes increased under OGD/R;however,the percentage was significantly decreased by the addition of CQ to HCN2-shRNA-transfected HT22 *** present re