DDAH1 promotes neurogenesis and neural repair in cerebral ischemia  

作　　者：Qiming Gao Pinfei Ni Yilin Wang Peiyun Huo Xiaojie Zhang Sihan Wang Fuyao Xiao Yixuan Li Wei Feng Juntao Yuan Teng Zhang Qiang Li Boyu Fan Yuhao Kan Zhirui Li Yimiao Qi Junfei Xing Zhenghong Yang Haixiao Cheng Xinran Gao Xiaoyan Feng Ming Xue Yang Liu Yumin Luo Zhongbing Lu Yuming Zhao 

机构地区：[1]Department of Pharmacology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China [2]Cerebrovascular Diseases Research Institute and Department of Neurology,Xuanwu Hospital of Capital Medical University,Beijing 100053,China [3]State Key Laboratory for Structural Chemistry of Unstable and Stable Species,Institute of Chemistry,Chinese Academy of Sciences,Beijing 100190,China [4]College of Life Science,University of Chinese Academy of Sciences,Beijing 100049,China [5]Department of Laboratory Animal,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China [6]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第5期2097-2118,共22页药学学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(32171237,82070250,82171301,82370275,32071126);Beijing Natural Science Foundation(7222010);the Fundamental Research Funds for the Central Universities.Thanks for the support of the undergraduate research training programs of Capital Medical University(XSKY2023,XSKY2022,XSKY2021),China.We sincerely acknowledged that Professor Jianwei Jiao from the Institute of Zoology,Chinese Academy of Sciences,kindly provided the Nestin-Cre(C57BL/6.Cg-Tg(Nes-Cre)1Kln/J)mice.We sincerely appreciate for the technical service and support from Tissue Gnostics Asia Pacific Limited in the image caption and data analysis of immunohistochemical staining analysis.

摘　　要：Choline acetyltransferase(ChAT)-positive neurons in neural stem cell(NSC)niches can evoke adult neurogenesis(AN)and restore impaired brain function after injury,such as acute ischemic stroke(AIS).However,the relevant mechanism by which ChAT+neurons develop in NSC niches is poorly understood.Our RNA-seq analysis revealed that dimethylarginine dimethylaminohydrolase 1(DDAH1),a hydrolase for asymmetric NG,NG-dimethylarginine(ADMA),regulated genes responsible for the synthesis and transportation of acetylcholine(ACh)(Chat,Slc5a7 and Slc18a3)after stroke insult.The dual-luciferase reporter assay further suggested that DDAH1 controlled the activity of ChAT,possibly through hypoxia-inducible factor 1α(HIF-1α).KC7F2,an inhibitor of HIF-1α,abolished DDAH1-induced ChAT expression and suppressed neurogenesis.As expected,DDAH1 was clinically elevated in the blood of AIS patients and was positively correlated with AIS severity.By comparing the results among Ddah1 general knockout(KO)mice,transgenic(TG)mice and wild-type(WT)mice,we discovered that DDAH1 upregulated the proliferation and neural differentiation of NSCs in the subgranular zone(SGZ)under ischemic insult.As a result,DDAH1 may promote cognitive and motor function recovery against stroke impairment,while these neuroprotective effects are dramatically suppressed by NSC conditional knockout of Ddah1 in mice.

关 键 词：DDAH1 NEUROGENESIS Neural repair CHAT HIF-1α ACH STROKE ADMA 

分 类 号：R743.3[医药卫生—神经病学与精神病学]