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-H3RCT414-436, 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.
Highlights
The role of the histamine H3 receptor (H3R) in cerebral ischaemia/reperfusion (I/R) injury remains unknown
We find that H3R antagonism and H3R deletion protect against I/R injury in a histamine-independent manner
In neurons after OGD/R, the viability declined to 62.84±2.70% of control (Fig. 1b, and thioperamide (H3R antagonist, 10 À 6 mol l À 1) rescued the viability to 87.07±2.14% (n 1⁄4 7, Po0.001), which was reversed by immepip (H3R agonist, 10 À 6 mol l À 1) to 67.82±2.75% (n 1⁄4 7 Po0.001, Fig. 1b)
Summary
The role of the histamine H3 receptor (H3R) in cerebral ischaemia/reperfusion (I/R) injury remains unknown. 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. The role of autophagy in ischaemia remains controversial, recent reports indicate that it is neuroprotective in moderate injury[24,26,27,28], and these investigations have given rise to the proposal that the injury can be rescued by inducing autophagy[28]. H3R antagonists reinforces I/R-induced autophagy and the neuroprotective effect of H3R antagonism is reversed by autophagy blockade. H3R aggravates ischaemic brain injury by histamine-independent mechanisms, and its antagonism may provide a novel neuroprotective strategy against cerebral ischaemia by regulating autophagy
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