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The role of the histamine H3 receptor(H3R)in cerebral ischemia remains entirely unknown.Here we found that H3R expression was upregulated after ischemia/reperfusion(I/R)both in transient middle cerebral artery occlusion and oxygen-glucose-deprivation/reperfusion models.Moreover,overexpression of H3R in HEK293 cells led to more cell death after serum deprivation.Either H3R antagonists(thioperamide,clobenpropit and A331440)or H3R knockout attenuated I/R-induced neuronal injury and apoptosis,which was reversed by the H3R selective agonist immepip.Interestingly,H1 and H2 receptor-antagonists,alphafluoromethylhistidine,a selective histidine decarboxylase(HDC)inhibitor,and HDC knockout all failed to compromise the protection by thioperamide.In addition,neuroprotection by the H3R antagonist against I/R was reversed by 3-methyladenine and siRNA for Atg7.In Atg5-/-mouse embryonic fibroblasts,the protection was also diminished.Furthermore,either the peptide Tat-H3RCT414-436,which blocks chloride intracellular channel 4(CLIC4)binding with the H3R,or siRNA for CLIC4 further increased I/R-induced autophagy and consequently protected against I/R injury.Therefore,we found for the first time that H3R promotes I/R injury,its inhibition is protective,and this is independent of histamine,but attributable to suppressed H3R/CLIC4 binding-induced autophagy.Our results strongly suggest that H3R inhibition may be attractive as a potential clinical therapeutic target for cerebral ischemia.