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

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. Histamine H3 receptor dysregulation is a hallmark of pathological conditions in the central nervous system, and H3 receptor antagonism is neuroprotective. Here Chen et al. show that histamine-independent H3 receptor activation can enhance neuronal cell death during cerebral ischaemia by suppressing autophagy.