We have reported that facilitation of central histaminergic activity prevents the development of
ischemia-induced
brain injury. Since
cerebral edema is a major cause of brain damage, we studied effects on
brain edema of postischemic administration of
L-histidine, a precursor of
histamine, and
thioperamide, a
histamine H(3)-receptor antagonist, both of which enhance central histaminergic activity. Focal
cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery in rats, and the water content and
infarct size were determined 24 h after reperfusion. Changes in the extracellular concentration of
histamine were examined in the striatum by a microdialysis procedure, and effects of these compounds were evaluated. Repeated administration of
L-histidine (1000 mg/kg x 2, i.p.), immediately and 6 h after reperfusion, reduced the increase in the water contents in ischemic regions. Simultaneous administration of
thioperamide (5 mg/kg, s.c.) with
L-histidine (1000 mg/kg, i.p.) completely prevented
edema formation and alleviated
brain infarction, although a single dose of
L-histidine, immediately after reperfusion, showed no benefits. The striatal
histamine level was gradually increased after reperfusion as well as during
ischemia. Simultaneous administration of
thioperamide with
L-histidine markedly increased the brain
histamine concentration, and the value increased up to 230% of that in the saline group 5 - 6 h after reperfusion.
L-Histidine alone did not affect the increase in the
histamine output after
ischemia. These findings suggest that further activation of the central histaminergic system after initiation of
cerebral ischemia prevents development of
ischemia-induced
brain edema.