title: Histamine up-regulates astrocytic glutamate transporter 1 and protects neurons against ischemic injury.
abstract: Astrocytic glutamate transporter 1 (GLT-1) is responsible for the majority of extracellular glutamate clearance and is essential for preventing excitotoxicity in the brain. Up-regulation of GLT-1 shows benefit effect on ischemia-induced neuronal damage. In present study, we examined the effect of histamine, a neurotransmitter or neuromodulator, on GLT-1 expression and function. In acute hippocampal slices, histamine selectively increased GLT-1 expression independent of neuronal activities. Similar up-regulation of GLT-1 was also observed after histamine treatment in pure cultured astrocytes, which was abolished by H1 receptor antagonist or PKC inhibitor. Cell surface biotinylation and whole-cell patch recordings of glutamate transporter current confirmed the up-regulation of functional GLT-1 following histamine exposure. Histamine treatment decreased the extracellular glutamate content and alleviated neuronal cell death induced by exogenous glutamate challenge. Moreover, we found a significant neuroprotective effect of histamine in brain slices after oxygen-glucose deprivation (OGD). In addition, histidine, the precursor of histamine, also showed neuroprotection against ischemic injury, which was accompanied by reversion of declined expression of GLT-1 in adult rats subjected to middle cerebral artery occlusion (MCAO). These neuroprotective effects of histamine/histidine were blocked by GLT-1 specific inhibitor dihydrokainate or H1 receptor antagonist. In summary, our results suggest that histamine up-regulates GLT-1 expression and function via astrocytic H1 receptors, thus resulting in neuroprotection against excitotoxicity and ischemic injury.
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, China.
authors.forename: Xiao-Fen
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Lou
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
authors.forename: Miao-Miao
authors.initials: MM
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Yan
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
authors.forename: Wei-Zheng
authors.initials: WZ
authors.lastname: Zeng
authors.affiliation: Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
authors.forename: Shi-Hong
authors.initials: SH
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Institute of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
authors.forename: Tian-Le
authors.initials: TL
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China. Electronic address: chenzhong@zju.edu.cn.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D018696:Neuroprotective Agents; D006632:Histamine
keywords: ACSF; CNS; DHK; EAAT; Excitotoxicity; GABA; GLAST; GLT-1; GS; Glutamate; Glutamate transporter 1; HTMT; Histamine; Ischemia; L-TBOA; L-threo-β-benzyloxyaspartate; MCAO; Neuroprotection; OGD; RIPA; SD; Sprague-Dawley; TTX; artificial cerebrospinal fluid; central nervous system; dihydrokainate; excitatory amino acid transporter; gamma-aminobutyric acid; glutamate aspartate transporter; glutamate transporter 1; glutamine synthetase; histamine trifluoromethyl toluidide; middle cerebral artery occlusion; oxygen-glucose deprivation; radioimmune precipitation assay; tetrodotoxin