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Background: Histamine is one of the most widely distributed neurotransmitter of neuromodulator and plays an important role in physiological and pathological processes in the central nervous system. It has been known that histamine protects against cerebral ischemia during the early stage. However, the role of histamine during the late stage of cerebral ischemia is still unclear. Considering the different targets of histamine to the early or late stage after ischemia, and bi-directional regulation of NMDA receptor which involved in the brain ischemia by histamine, we use different administration schedules to study the effect of histidine, a precursor of histamine, which enhances central histaminergic activity, on the long-term injury after cerebral ischemia.Methods: SD rats were divided into sham-operated group, ischemic model group and four treatment groups, and treatment groups using different administrations: His 1000-0, only given high-dose of histidine of 1000 mg/kg during the early stage; His 500-500, given low-dose histidine of 500 mg/kg throughout the course of brain ischemia; His 1000-500, given high-dose histidine of 1000 mg/kg during the early stage and low-dose histidine of 500 mg/kg during the late stage; and His 1000-1000, given high-dose histidine of 1000 mg / kg throughout the course of brain ischemia. At different time points after ischemia, behavioral change, infarct size and glial scar area were evaluated in each group.Results: Administration of histidine significantly alleviated long-term cerebral injury caused by cerebral ischemia. His 1000-500 improved the neurological score and reduced the locomotor activity on day 14, day 28, day 42, day 56 after ischemia, In addition, His 500-500 also reduced the locomotor activity on day 14, day 42, and day 56, while His 1000-1000 also reduced the locomotor activity on day 14. On fear conditioning, His 1000-500 significantly improved the context memory and cue memory on day 28 and day 56, while His 500-500 improved the cue memory on day 28, and His 1000-1000 improved the context memory on day 56. On spatial learning and memory, His 1000-500 significantly improved memory on day 28, while His 1000-500 and His 500-500 considerably improved memory on day 56. On infarct area, only His 1000-500 significantly reduces infarct size on day 28 and day 56. On the glial scar area, His 1000-500 significantly reduced glial scar area, and His 500-500 also reduced the glial scar on day 28.Conclusions: The study found that histidine markedly protects against the long-term injury after cerebral ischemia on neurological score, learing and memory, infarct area, and glial scar area. The administration of histidine with 1000 mg/kg at the early stage, and 500 mg/kg at the late stage, showed the most obvious protective effect. Maybe different doses of histidine have different mechanisms at the early and late stages. And this will provide a new strategy for clinical treatment.
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