Selective histamine H2 receptor agonists alleviate blood-brain barrier disruption by promoting the expression of vascular protective factors following traumatic brain injury in mice

Abstract

Histamine is a major neurotransmitter and alleviates neuronal damage after ischemic injury via H₂ receptors. Herein, we investigated the effects of H₂ receptor agonists on the blood-brain barrier (BBB) disruption after traumatic brain injury (TBI). Male ddY mice were used to generate the TBI model, in which a fluid percussion injury (FPI) was induced by a hydraulic impact. The BBB disruption was evaluated using Evans blue extravasation. H₂ receptor agonists, amthamine and dimaprit, were administered into the lateral cerebroventricle (i.c.v.) or tail vein (i.v.) from 3 hours to 3 days after FPI. The i.c.v. or i.v. administration of amthamine and dimaprit reduced FPI-induced Evans blue extravasation and promoted mRNA expression of vascular protective factors, including angiopoietin-1 and sonic hedgehog. The co-administration of ranitidine, a H₂ receptor antagonist, inhibited these effects. Expression of the H₂ receptor was observed in astrocytes and brain microvascular endothelial cells (BMECs) in the injured cortex. Treatment with amthamine and dimaprit promoted mRNA expression of vascular protective factors in astrocytes and BMECs. These results suggest that H₂ receptor agonists alleviate TBI-induced BBB disruption by increasing the expression of vascular protective factors in astrocytes and BMECs.