Inflammation is a crucial factor in the development of
ischemia-induced
brain injury. Since facilitation of central histaminergic activity ameliorates
reperfusion injury, effects of postischemic administration of
L-histidine, a precursor of
histamine, and
thioperamide, a
histamine H3 receptor antagonist, on inflammatory cell infiltration were evaluated in a rat model of transient occlusion of the middle cerebral artery. After reperfusion for 12, 24, or 72 h following 2 h of occlusion, brain slices were immunohistochemically stained with
antibodies against
myeloperoxidase and CD68, which were markers of polymorphonuclear leukocytes and macrophages/microglia, respectively. After reperfusion for 12-24 h, the number of neutrophils on the ischemic side increased markedly, whereas the increase was not observed on the contralateral side. Administration of
L-histidine (1000 mg/kg x 2, i.p.), immediately and 6 h after reperfusion, reduced the number of neutrophils to 52%. Simultaneous administration of
thioperamide (5 mg/kg, s.c.) further decreased the number of neutrophils to 32%. Likewise, the
ischemia induced increase in the number of CD68-positive cells after 24 h was suppressed by
L-histidine injections. The
L-histidine administration decreased the number of CD4+ T lymphocytes on both ischemic and contralateral sides after 12 h, and concurrent administration of
thioperamide prolonged the effect. Although administration of
mepyramine (3 nmol, i.c.v.) did not affect suppression of leukocyte infiltration,
ranitidine tended to reverse the effect of
L-histidine. These data suggest that enhancement of central histaminergic activity suppresses inflammatory cell recruitment after ischemic events through
histamine H2 receptors, which may be a mechanism underlying the protective effect of
L-histidine.