Reduction of the infarct size by simultaneous administration of l-histidine and diphenhydramine in ischaemic rat brains

Aims: While diphenhydramine is a histamine H₁ receptor antagonist, the agent has been shown to inhibit histamine-N-methyltransferase, a histamine inactivating enzyme in the brain. Since an increase in the brain concentration of histamine ameliorates reperfusion injury after cerebral ischaemia, effects of postischaemic administration of diphenhydramine were evaluated in rats treated with l-histidine, a precursor of histamine. Methods: The right middle cerebral artery was occluded for 2. h, and the infarct size was determined 24. h after reperfusion of cerebral blood flow. Brain oedema was evaluated by comparing the area of the right hemisphere to that of the left hemisphere. Results: Focal cerebral ischaemia provoked marked damage in saline-treated control rats, and infarct volumes in the striatum and cerebral cortex were 56 (49-63) mm³ and 110 (72-148) mm³, respectively (means and 95% confidence intervals, n=6). Administration of l-histidine (1000mg/kg, intraperitoneal) immediately after reperfusion did not affect the infarct size. Simultaneous administration of diphenhydramine (20mg/kg, intraperitoneal) with l-histidine reduced the infarct size to 25% and 21% of that in the control group, respectively. The combination therapy completely reduced ischaemia-induced brain oedema. Conclusion: Because histamine H₁ action does not influence ischaemic brain damage, elevation of the central histamine concentration by blockade of histamine-N-methyltransferase may be a likely mechanism responsible for the alleviation.