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首页> 外文期刊>Epilepsia: Journal of the International League against Epilepsy >Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation
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Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation

机译：抑制雷帕霉素的哺乳动物靶标可减少癫痫发生和血脑屏障渗漏，但不会减少小胶质细胞活化

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Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy. Methods: Rats were treated with rapamycin or vehicle once daily for 7 days (6 mg/kg/day, i.p.) starting 4 h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6 weeks after SE. Video-electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood-brain barrier leakage. Key Findings: Rapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin-treated rats developed hardly (n = 9) or no (n = 3) seizures during the 6-week treatment, whereas vehicle-treated rats showed a progressive increase of seizures starting 1 week after SE (mean 8 ± 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin-treated rats versus vehicle-treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post-SE groups. Of interest, blood-brain barrier leakage was barely detected in the rapamycin-treated group, whereas it was prominent in the vehicle-treated group. Significance: mTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood-brain barrier leakage in rapamycin-treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined.
机译：目的：先前的研究表明，在大鼠颞叶癫痫模型中，用雷帕霉素抑制雷帕霉素（mTOR）途径的哺乳动物靶标可预防药理学诱发癫痫持续状态（SE）后的癫痫发生。由于雷帕霉素还因其免疫抑制特性而闻名，因此我们推测雷帕霉素发挥这种作用的机制之一可能是通过抑制脑部炎症，而这一过程被认为在癫痫的发生和发展中起主要作用。方法：SE诱导后4小时开始，每天用雷帕霉素或溶媒治疗大鼠一次，共7天（6 mg / kg /天，腹腔注射），这是通过电刺激角束诱发的。此后，每隔一天施用雷帕霉素，直至SE后6周处死大鼠。电视脑电图用于监测癫痫发作的发生。通过免疫组织学染色评估神经元死亡，突触重组，小胶质细胞和星形胶质细胞活化。给予荧光素以定量血脑屏障渗漏。关键发现：雷帕霉素治疗与媒介物治疗大鼠相比并没有改变SE的严重程度和持续时间。雷帕霉素治疗的大鼠在6周治疗期间几乎没有发作（n = 9）或没有癫痫发作（n = 3），而媒介物治疗的大鼠在SE后1周开始显示癫痫发作逐渐增加（平均每天8±2次癫痫发作）在第六周）。 SE后通常发生的细胞损失和发芽显着，但雷帕霉素治疗的大鼠平均低于运载体治疗的大鼠。然而，各种炎症标志物（CD11b / c和CD68）被显着上调，并且在SE后组之间没有显着差异。令人感兴趣的是，在雷帕霉素治疗组中几乎未检测到血脑屏障渗漏，而在媒介物治疗组中则明显。意义：尽管存在小胶质细胞激活，但mTOR抑制仍导致癫痫发作的强烈减少，这表明雷帕霉素对癫痫发作的影响不是由于炎症的控制。还需要确定对雷帕霉素治疗的大鼠血脑屏障渗漏的影响是药物抑制癫痫发作的结果的结果，还是真正的抗癫痫作用。

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