凝血酶对脑组织毒性损伤机制及水蛭素、尼莫地平干预作用的研究

目的 探讨凝血酶对脑组织损害的机制，及凝血酶抑制剂水蛭素和尼莫地平对其的影响。方法 将不同剂量的凝血酶或／和水蛭素注入SD大鼠尾状核，尼莫地平腹腔注射。采用干湿重法、免疫组化法、原位末端缺口标记法及镜下观察在不同时点大鼠脑含水量、细胞骨架蛋白、神经元凋亡数及组织学改变。结果 （1）大剂量凝血酶组出现以下改变：早期（4h）明显味水肿，其高峰时间为24～48h，3d后水肿逐渐消退，7d趋于正常；细胞骨架蛋门出现不同程度变形甚至崩解，24h损伤进一步加重，导致不可逆损伤，3～7d神经细胞坏死；神经细胞凋亡，其高峰时间为24～48h，持续到7d；小剂量凝血酶组及生理盐水组无以上作用。（2）水蛭素能特异性抑制凝血酶的作用，而钙离子拈抗剂可减轻或延迟细胞的损伤。结论 大剂量凝血酶可导致脑水肿、脑细胞不同逆损伤及脑细胞凋亡，其高峰时间均在24～48h。早期干预可改善脑出血（ICH）后血肿周围脑组织水肿和继发性神经几损伤，改善ICH的预后。

Study of the mechanism of brain injury caused by thrombin and the intervention effect of hirudin and nimodipine

Objective To investigate the mechanism of brain injury caused by thrombin and the intervention effect of hirudin and nimodipine.Methods Different doses of thrombin or/and hirudin were injected into nucleus caudatus of SD rats,nimodipine was given intraperitoneally.Dry-wet-weighing technique,immunohistochemical method and TUNEL were used to examine brain edema,the changes of cytoskeleton,neuron apoptosis and histological changes.Results(1) High dose of thrombin resulted in severe cerebral edema as early as 4 h after injection and the maximum edema occurred at 24~48 h.The edema gradually decreased and got close to normal within 3~7 d.Cytoskeleton changes were observed at early stage(4h),reversible or irreversible injuries presented at 24~48 h,and neuron necrosis occurred within 3~7 d.Neuron apoptosis started at 4h and peaked at 24~48 h.In contrast,low dose of thrombin and normal saline did not show these effects.(2) The effects of thrombin could be inhibited by hirudin and nimodipine(a calcium-ion antagonist) could relieve or delay cell injury.Conclusions High dose of thrombin may result in severe brain edema,neuron irreversible injury and apoptosis,which all peak at 24~48 h.Early treatments could greatly reduce brain damage and improve prognosis of intracerebral hemorrhage.