title: Histamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms.
abstract: The role of the histamine H3 receptor (H3R) in cerebral ischaemia/reperfusion (I/R) injury remains unknown. Here we show that H3R expression is upregulated after I/R in two mouse models. H3R antagonists and H3R knockout attenuate I/R injury, which is reversed by an H3R-selective agonist. Interestingly, H1R and H2R antagonists, a histidine decarboxylase (HDC) inhibitor and HDC knockout all fail to compromise the protection by H3R blockade. H3R blockade inhibits mTOR phosphorylation and reinforces autophagy. The neuroprotection by H3R antagonism is reversed by 3-methyladenine and siRNA for Atg7, and is diminished in Atg5⁻/⁻ mouse embryonic fibroblasts. Furthermore, the peptide Tat-H3R(CT414-436), which blocks CLIC4 binding with H3Rs, or siRNA for CLIC4, further increases I/R-induced autophagy and protects against I/R injury. Therefore, H3R promotes I/R injury while its antagonism protects against ischaemic injury via histamine-independent mechanisms that involve suppressing H3R/CLIC4 binding-activated autophagy, suggesting that H3R inhibition is a therapeutic target for cerebral ischaemia.
authors.affiliation: 1] Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China [2].
authors.forename: Haijing
authors.initials: H
authors.lastname: Yan
authors.affiliation: 1] Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China [2] Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, Zhejiang, China [3].
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1] Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China [2] Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, Zhejiang, China [3].
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xingzhou
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1] Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China [2] Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China [2] Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, China.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Gao
authors.affiliation: 1] Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China [2] 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: Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lv
authors.affiliation: Department of Engineering, School of Medicine, Tohoku University, Aoba-ku, Sendai 980-8775, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.affiliation: Laboratory of Molecular Neuropathology, Department of Pharmacology, Soochow University, College of Pharmaceutical Sciences, Suzhou 215123, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.affiliation: 1] Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China [2] Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, Zhejiang, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000071187:Autophagy-Related Protein 5; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D006632:Histamine / Q000378:metabolism*; D017442:Histamine Agonists / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C479423:CLIC protein, mouse; D018118:Chloride Channels; D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D018100:Receptors, Histamine H3; D006632:Histamine; D006640:Histidine Decarboxylase