Cerebral ischemia induces excess release of
glutamate and an increase in the intracellular Ca(2+) concentration in neurons, which provokes enzymatic process leading to irreversible neuronal injury.
Histamine plays a role as a
neurotransmitter in the mammalian brain, and histamine release from nerve endings is enhanced in
ischemia by facilitation of histaminergic activity. Dissimilar to
ischemia-induced release of
glutamate, histamine release is gradual and long lasting. The enhancement may contribute to neuroprotection against ischemic damage, because suppression of histaminergic activity aggravates the histologic outcome caused by
ischemia. Preischemic administration of
histamine (i.c.v.) suppresses ischemic release of
glutamate and ameliorates neuronal damage, whereas blockade of central
histamine H(2) receptors aggravates ischemic injury. These suggest that
histamine provides beneficial effects against ischemic damage through
histamine H(2) receptors, when administered before induction of
ischemia. Postischemic loading with
histidine, a precursor of
histamine, alleviates both
brain infarction and delayed neuronal death. Since the alleviation is abolished by blockade of central
histamine H(2) receptors, facilitation of central
histamine H(2) action caused by
histidine may prevent
reperfusion injury after ischemic events. Because the
ischemia-induced increase in the
glutamate level rapidly resumes after reperfusion of cerebral blood flow, beneficial effects caused by postischemic loading with
histidine may be due to other mechanisms besides suppression of excitatory
neurotransmitter release. Anti-inflammatory action by
histamine H(2) receptor stimulation is a likely mechanism responsible for the improvement.