Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte mig

• 作 者: Ru-jia Liao Lei Jiang Rong-rong Wang Hua-wei Zhao Ying Chen Ya Li Lu Wang Yu-dong Zhou Xiang-nan Zhang Zhong Chen Wei-wei Hu
• 机 构: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of Chin
• 出 处: 第十六届全国神经精神药理学学术会议
• 发表日期: 2014年3期
• 关键词: Astrocyte Cerebral ischemia Glial scar Histamine Migration Neuroprotection

　　Currently effective neuroprotective agents are still not availablefor cerebral ischemia, probably due to its complicated pathophysiological events that evolve temporally and spatially.Histamine showed potential protective effect on neurons, astrocytes, and inflammatory cell at early stage after cerebral ischemia, however, its long-term action is not characterized.Regarding the investigation onmultiple actions of histamine on cerebral ischemia, various administration regimens were constructed for histidine, which is a precursor of histamine.Among the different histidineregimens, the treatment with high dose at early stage but low dose at late stage demonstrated the most remarkablelong-term protection against the injury,in terms of infarct area, neurological deficit score andcognitive function (in Morris water maze and fear conditioning test).Furthermore, this treatmentregimen also robustly reduced the size of glial scar area, along with the promotion of astrocyte migration towards the infarct core, which was presented by the redistribution of reactive astrocytes and higher ratio of polarized astrocytes.In wound-healing assay and transwell test in vitro, histamine promoted astrocyte migration, together with polarized morphology and lamellipodia formation.This promotion on astrocyte migration can be reversed by H2 antagonists cimetidine and famotidine, and PKA inhibitor Rp-cAMP.The GTP-bound active form of small GTPase rac1 was up-regulated by histamine, while a specific inhibitor of rac1,NSC23766, abrogated the promotive effect of histamine on astrocyte migration or neuroprotection from histidine.Our data indicated that a dose and stage dependent histidine treatment promoted astrocyte migration towards the infarct corebenefiting long-term neurologicalfunction recovery aftercerebral ischemia through H2 receptor and subsequent up-regulation of active rac1.This therapeutic regimen may also bring a new dose and stage dependent strategy for the cerebral ischemia therapy, especially related to the function of astrocytes.