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Nat Commun. 2014 Feb 25;5:3334. doi: 10.1038/ncomms4334.

Histamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms.

Author information

1
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].
2
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].
3
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.
4
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.
5
Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, China.
6
Department of Engineering, School of Medicine, Tohoku University, Aoba-ku, Sendai 980-8775, Japan.
7
Laboratory of Molecular Neuropathology, Department of Pharmacology, Soochow University, College of Pharmaceutical Sciences, Suzhou 215123, China.
8
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.

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.

PMID:
24566390
PMCID:
PMC3948077
DOI:
10.1038/ncomms4334
[Indexed for MEDLINE]
Free PMC Article

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