Ischemic stroke is a disease with high mortality and a main leading cause of disability.However,few effective therapeutic approaches are available at present.This may attribute to the complex pathological process of cerebral ischemia.Therefore,the multiple therapeutic requirements with multiple targets in individual stage are needed.Brain histaminergic system is important in regulating physiological functions.We found that activating histaminergic system in brain is effective in rescuing acute ischemic neuronal injury,either by direct inhibition of excitotocixity or regulating astrocytes glutamate metabolism.Further works revealed that both carnosine,the precursor of histamine,and H3R antagonist,potentiation histamine release,act in a histamine-independent manner.Instead,antioxidation and H3R-mediated autophagy reinforcement may underly their neuroprotection(unpublished data).Histamine also provides therapy opportunities in recovery phase after cerebral ischemia.Our recent data suggested that histamine may prevent the glial scar formation and consequently improve neurons regeneration.Interestingly,we found a variety of dosage combination of histidine in different phase of recovery will further improve the effects of inhibiting glial scar.Histamine may direct regulating matrix proteins expression and promoting astrocytes migration to ischemic region via H2R signaling in early and late phase,respectively.Besides the external activation of histaminergic system,histamine is involved in endogenous protective strategy as well.We reported that hypoxic preconditioning protects against cerebral ischemia in histamine-VEGF signaling pathway.Further works indicated that low glucose and acidosis postconditioning also provide robust neuronal protection,although histamine may not be involved in these context(unpublished data).These important histamine-independent pathologcal characteristics of brain ischemia may be valuable in developing novel therapeutic strategies.In conclusion,our investigations provide evidences indicating that activation of brain histaminergic system protects against ischemic neuronal injury in distinct pathological stages.These data shed light on the role of histaminergic system as potential multiple therapeutic targets in cerebral ischemia. Ischemic stroke is a disease with high mortality and a major leading cause of disability. However, few effective therapeutic approaches are available at present. This may attribute to the complex pathological process of cerebral ischemia. Before, the multiple therapeutic requirements with multiple targets in individual stage are needed. Brain histaminergic system is important in regulating physiological functions. We found that activating histaminergic system in brain is effective in rescuing acute ischemic neuronal injury, either by direct inhibition of excitotocixity or regulating astrocytes glutamate metabolism. Further works revealed that both both carnosine, the precursor of histamine, and H3R antagonist, potentiation histamine release, act in a histamine-independent manner. Instead, Antioxidation and H3R-mediated autophagy reinforcement may underly their neuroprotection (unpublished data). Histamine also provides therapy opportunities in recovery phase after cerebral ischemia .Our recent data suggest ed that histamine may prevent the glial scar formation and due improve neurons regeneration.Interestingly, we found a variety of dosage combination of histidine in different phase of recovery will further improve the effects of inhibiting glial scar. Histamine may direct regulating matrix proteins expression and promoting astrocytes migration to ischemic region via H2R signaling in early and late phase, respectively .esides the external activation of histaminergic system, histamine is involved in endogenous protective strategy as well. We reported that hypoxic preconditioning protects against cerebral ischemia in histamine-VEGF signaling pathway. Further works indicated that low glucose and acidosis postconditioning also provide robust neuronal protection, although histamine may not be involved in these contexts (unpublished data). The important histamine-independent pathologcal characteristics of brain ischemia may be valuable in developing novel therapeutic strategies. ,our investigations provide evidences indicating that activation of brain histaminergic system protects against ischemic neuronal injury in distinct pathological stages. the data shed light on the role of histaminergic system as potential multiple therapeutic targets in cerebral ischemia.