Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia
Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia
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DOI：
10.1016/s0006-8993(98)00126-7
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发表时间：
1998-05-04
期刊：
影响因子：
2.9
通讯作者：
Kimura, J
中科院分区：
文献类型：
--
作者：
Wakita, H;Tomimoto, H;Kimura, J
免疫抑制剂在脑缺血中的神经保护作用已被证明。为了探讨免疫抑制剂在慢性脑缺血中的作用，并设计一种具有安全治疗窗的药物方案，我们观察了一种有效的免疫抑制剂FK506对慢性脑缺血的作用。雄性Wistar大鼠73只，结扎双侧颈总动脉。其中58只大鼠接受FK506(0.2、0.5、1.0 mg/kg)慢性注射，其余15只接受赋形剂溶液注射。小胶质细胞/巨噬细胞采用免疫组织化学方法检测白细胞共同抗原和主要组织相容性复合体，星形胶质细胞以胶质纤维酸性蛋白为标记物。于结扎后7~30d检测脑白质稀疏程度和免疫阳性神经胶质细胞数。给药组动物脑白质中的小胶质/巨噬细胞和星形胶质细胞持续广泛激活，包括视神经、视束、胼胝体、内囊、前连合和尾壳横行纤维束。在FK506处理的大鼠中，激活的小胶质细胞/巨噬细胞的数量显著减少，与赋形剂处理的大鼠相比，呈剂量依赖关系(p<；0.01)。FK506还以剂量依赖的方式抑制白质稀疏(p<；0.01)。因此，临床相关剂量的FK506减轻了慢性脑缺血大鼠的胶质细胞激活和脑白质变化。这些结果提示FK506在脑血管疾病中有潜在的应用前景。(C)1998年爱思唯尔科学公司。
Neuroprotective effects of immunosuppressive agents have been shown in cerebral ischemia. To investigate the role of immunosuppressive agents in chronic cerebral ischemia and to design a drug protocol with safe therapeutic windows, we examined the effects of FK506, a potent immunosuppressive agent, on chronic cerebral ischemia. Both common carotid arteries were ligated in 73 male Wistar rats. Fifty-eight of these rats received a chronic injection of FK506 (0.2, 0.5, 1.0 mg/kg) and the remaining 15 received a vehicle solution injection. Microglia/macrophage was investigated with immunohistochemistry for leukocyte common antigen and major histocompatibility complex, and astroglia was examined with glial fibrillary acidic protein as markers. White matter rarefaction and the number of immunopositive glial cells were assessed from 7 to 30 days after the ligation. In the vehicle-treated animals, there was persistent and extensive activation of the microglia/macrophages and astroglia in the white matter, including the optic nerve, optic tract, corpus callosum, internal capsule, anterior commissure and traversing fiber bundles of the caudoputamen. In the FK506-treated rats, the number of activated microglia/macrophages was significantly reduced in a dose-dependent manner(p < 0.01) as compared to the vehicle-treated rats. Rarefaction of the white matter was also inhibited by FK506 in a dose-dependent manner (p < 0.01). Thus, a clinically-relevant dosage of FK506 attenuated both glial activation and white matter changes in chronic cerebral ischemia in the rat. These results indicate a potential use for FK506 in cerebrovascular diseases. (C) 1998 Elsevier Science B.V.