Histamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms
書誌事項
- 公開日
- 2014-02-25
- 資源種別
- journal article
- 権利情報
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- http://creativecommons.org/licenses/by/3.0
- DOI
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- 10.1038/ncomms4334
- 公開者
- Springer Science and Business Media LLC
説明
<jats:title>Abstract</jats:title><jats:p>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<jats:italic>Atg7</jats:italic>, and is diminished in<jats:italic>Atg5</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>mouse embryonic fibroblasts. Furthermore, the peptide Tat-H3R<jats:sub>CT414-436</jats:sub>, which blocks CLIC4 binding with H3Rs, or siRNA for<jats:italic>CLIC4</jats:italic>, 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.</jats:p>
収録刊行物
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- Nature Communications
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Nature Communications 5 (1), 2014-02-25
Springer Science and Business Media LLC
