Protection against glutathione depletion-associated oxidative neuronal death by neurotransmitters norepinephrine and dopamine:Protein disulfide isomerase as a mechanistic target for neuroprotection  

作　　者：Hye Joung Choi Tong-xiang Chen Ming-Jie Hou Ji Hoon Song Peng Li Chun-feng Liu Pan Wang Bao Ting Zhu 

机构地区：[1]Shenzhen Key Laboratory of Steroid Drug Discovery and Development,School of Medicine,The Chinese University of Hong Kong,Shenzhen 518172,China [2]Department of Pharmacology,Toxicology and Therapeutics,School of Medicine,University of Kansas Medical Center,Kansas City,KS 66160,USA [3]Institute of Neuroscience,Soochow University,and Department of Neurology,Second Affiliated Hospital of Soochow University,Suzhou 215004,China

出　　处：《Acta Pharmacologica Sinica》2022年第10期2527-2541,共15页中国药理学报（英文版）

基　　金：This study is supported,in part,by the University of Kansas Medical Center Endowment Fund,and by research grants from Shenzhen Key Laboratory of Steroid Drug Discovery and Development(grant#ZDSYS20190902093417963);the National Natural Science Foundation of China(grant#81630096)。

摘　　要：Oxidative stress is extensively involved in neurodegeneration.Clinical evidence shows that keeping the mind active through mentally-stimulating physical activities can effectively slow down the progression of neurodegeneration.With increased physical activities,more neurotransmitters would be released in the brain.In the present study,we investigated whether some of the released neurotransmitters might have a beneficial effect against oxidative neurodegeneration in vitro.Glutamate-induced,glutathione depletion-associated oxidative cytotoxicity in HT22 mouse hippocampal neuronal cells was used as an experimental model.We showed that norepinephrine(NE,50μM)or dopamine(DA,50μM)exerted potent protective effect against glutamate-induced cytotoxicity,but this effect was not observed when other neurotransmitters such as histamine,γ-aminobutyric acid,serotonin,glycine and acetylcholine were tested.In glutamate-treated HT22 cells,both NE and DA significantly suppressed glutathione depletion-associated mitochondrial dysfunction including mitochondrial superoxide accumulation,ATP depletion and mitochondrial AIF release.Moreover,both NE and DA inhibited glutathione depletion-associated MAPKs activation,p53 phosphorylation and GADD45αactivation.Molecular docking analysis revealed that NE and DA could bind to protein disulfide isomerase(PDI).In biochemical enzymatic assay in vitro,NE and DA dose-dependently inhibited the reductive activity of PDI.We further revealed that the protective effect of NE and DA against glutamate-induced oxidative cytotoxicity was mediated through inhibition of PDI-catalyzed dimerization of the neuronal nitric oxide synthase.Collectively,the results of this study suggest that NE and DA may have a protective effect against oxidative neurodegeneration through inhibition of protein disulfide isomerase and the subsequent activation of the MAPKs‒p53‒GADD45αoxidative cascade.

关 键 词：NOREPINEPHRINE DOPAMINE glutamate oxidative neurodegeneration glutathione MAPKs‒p53‒GADD45α 

分 类 号：R965[医药卫生—药理学]