Ischemic stroke is a disease with high mortality and a main leading cause of disabihty.However, few effective thera peutic approaches are available at present.This may attribute to the complex pathological process of cerebral ischemia.There fore, the multiple therapeutic requirements with multiple targets in individual stage are needed.Brain histaminergic system is im portant in regulating physiological functions.We found that acti vating histaminergic system in brain is effective in rescuing acute ischemic neuronal injury, either by direct inhibition of excitoto cixity or regulating astrocytes glutamate metabolism.Further works revealed that both carnosine, the precursor of histamine,and H3R antagonist, potentiation histamine release, act in a his tamine-independent manner.