Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism
Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism
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DOI：
10.1161/strokeaha.107.495820
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发表时间：
2008-03-01
期刊：
影响因子：
8.3
通讯作者：
Fujiwara, Michihiro
中科院分区：
文献类型：
--
作者：
Hayakawa, Kazuhide;Mishima, Kenichi;Fujiwara, Michihiro
背景和目的 - 米诺环素是一种半合成四环素抗生素，据报道可改善局灶性脑缺血后的脑损伤并抑制小胶质细胞活化。然而，米诺环素的脑保护机制仍不清楚。在本研究中，我们研究了米诺环素在 4 小时大脑中动脉 (MCA) 闭塞小鼠模型中的作用机制。方法 - 4 小时 MCA 闭塞后一天，腹腔注射米诺环素，持续 14 天。脑缺血后 1、7 和 14 天测量神经系统评分。第 14 天时通过 10 rpm 的旋转杆测试评估运动协调性。还通过免疫染色和蛋白质印迹评估了活化的小胶质细胞和高迁移率族蛋白1 (HMGB1)（一种细胞因子样介质）。此外，在脑缺血后 14 天进行末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记免疫染色。 结果 - 重复使用米诺环素（1、5 和 10 mg/kg）治疗 14 天，神经系统评分、旋转棒测试运动协调性和生存率呈剂量依赖性改善。通过免疫染色和蛋白质印迹评估，米诺环素降低了 Iba1 的表达，Iba1 是活化小胶质细胞的标志物。此外，米诺环素降低了大脑内表达 HMGB1 的小胶质细胞的激活，并降低了大脑和血浆 HMGB1 水平。此外，米诺环素显着减少末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记阳性细胞的数量，并在脑缺血 14 天后预防缺血性脑萎缩。结论 - 我们的结果表明，米诺环素抑制表达 HMGB1 的活化小胶质细胞，并减少脑缺血引起的神经功能损伤。米诺环素将具有姑息作用，并为通过 HMGB1 抑制机制治疗缺血后损伤开辟新的治疗可能性。
Background and Purpose - Minocycline, a semisynthetic tetracycline antibiotic, has been reported to ameliorate brain injury and inhibit microglial activation after focal cerebral ischemia. However, the cerebroprotective mechanism of minocycline remains unclear. In the present study, we investigated that mechanism of minocycline in a murine model of 4-hour middle cerebral artery (MCA) occlusion.Methods - One day after 4-hour MCA occlusion, minocycline was administered intraperitoneally for 14 days. Neurologic scores were measured 1, 7, and 14 days after cerebral ischemia. Motor coordination was evaluated at 14 days by the rota-rod test at 10 rpm. Activated microglia and high-mobility group box1 (HMGB1), a cytokine-like mediator, were also evaluated by immunostaining and Western blotting. In addition, terminal deoxynucleotidyl transferase - mediated dUTP nick end-labeling immunostaining was carried out 14 days after cerebral ischemia.Results - Repeated treatment with minocycline (1, 5, and 10 mg/kg) for 14 days improved neurologic score, motor coordination on the rota-rod test, and survival in a dose-dependent manner. Minocycline decreased the expression of Iba1, a marker of activated microglia, as assessed by both immunostaining and Western blotting. Moreover, minocycline decreased the activation of microglia expressing HMGB1 within the brain and also decreased both brain and plasma HMGB1 levels. Additionally, minocycline significantly decreased the number of terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling - positive cells and prevented ischemic brain atrophy 14 days after cerebral ischemia.Conclusions - Our results suggest that minocycline inhibits activated microglia expressing HMGB1 and decreases neurologic impairment induced by cerebral ischemia. Minocycline will have a palliative action and open new therapeutic possibilities for treatment of postischemic injury via an HMGB1-inhibiting mechanism.