A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window
A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window
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DOI：
10.1073/pnas.96.23.13496
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发表时间：
1999-11-09
影响因子：
11.1
通讯作者：
Koistinaho, J
中科院分区：
文献类型：
--
作者：
Yrjänheikki, J;Tikka, T;Koistinaho, J
急性缺血性脑卒中患者的唯一治疗方法是溶栓治疗，但仅对一小部分脑卒中患者有效。人体和实验研究都表明，缺血性卒中涉及继发性炎症，这对缺血性损伤后的预后有重要影响。二甲胺四环素是一种半合成的第二代四环素，其抗炎作用与抗菌作用完全分离。由于四环素治疗在临床上耐受性良好，我们研究了二甲胺四环素是否具有较宽的治疗窗口保护局灶性脑缺血。我们使用一种暂时性大脑中动脉闭塞的大鼠模型，我们发现每天使用米诺环素在缺血前12小时治疗可使皮质梗死体积减少76 +/- 22%，在缺血后4小时开始治疗可使皮质梗死体积减少63 +/- 35%。降低环氧化酶-2的表达和前列腺素E-2的产生。米诺环素对星形胶质细胞增生或扩散性抑郁无影响，扩散性抑郁是一种被认为有助于皮质梗死扩大的离子瞬变波。二甲胺四环素治疗可能直接作用于脑细胞，因为培养的原代神经元也从谷氨酸毒性中抢救出来。二甲胺四环素可能代表抗炎化合物的原型，提供对缺血性中风的保护，并具有临床相关的治疗窗口。
The only treatment of patients with acute ischemic stroke is thrombolytic therapy, which benefits only a fraction of stroke patients. Both human and experimental studies indicate that ischemic stroke involves secondary inflammation that significantly contributes to the outcome after ischemic insult. Minocycline is a semisynthetic second-generation tetracycline that exerts antiinflammatory effects that are completely separate from its antimicrobial action. Because tetracycline treatment is clinically well tolerated, we investigated whether minocycline protects against focal brain ischemia with a wide therapeutic window. Using a rat model of transient middle cerebral artery occlusion, we show that daily treatment with minocycline reduces cortical infarction volume by 76 +/- 22% when the treatment is started 12 h before ischemia and by 63 +/- 35% when started even 4 h after the onset of ischemia, The treatment inhibits morphological activation of microglia in the area adjacent to the infarction, inhibits induction of IL-lp-converting enzyme, and reduces cyclooxygenase-2 expression and prostaglandin E-2 production. Minocycline had no effect on astrogliosis or spreading depression, a wave of ionic transients thought to contribute to enlargement of cortical infarction. Treatment with minocycline may act directly on brain cells, because cultured primary neurons were also salvaged from glutamate toxicity. Minocycline may represent a prototype of an antiinflammatory compound that provides protection against ischemic stroke and has a clinically relevant therapeutic window.