The cortical innate immune response increases local neuronal excitability leading to seizures
The cortical innate immune response increases local neuronal excitability leading to seizures
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DOI：
10.1093/brain/awp177
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发表时间：
2009-09-01
期刊：
影响因子：
14.5
通讯作者：
Barth, Daniel S.
中科院分区：
文献类型：
--
作者：
Rodgers, Krista M.;Hutchinson, Mark R.;Barth, Daniel S.
脑胶质细胞比神经元多五倍，最近因其可能参与癫痫发作而受到关注。小胶质细胞和星形胶质细胞与炎症性先天免疫反应有关，负责监测经常导致癫痫发作的脑损伤。因此，有人提出了一个有趣的建议，即癫痫发作可能是由大脑免疫反应促进和触发的。事实上，最近的证据强烈暗示先天免疫应答在癫痫实验模型中降低癫痫发作阈值，然而，没有证据表明它们可以在体内引发癫痫发作中发挥独立作用。在这里，我们表明，皮质先天免疫反应单独产生深刻的大脑兴奋性增加，导致局灶性癫痫发作。我们发现，皮质应用脂多糖，结合到Toll样受体4（TLR 4），三倍诱发场电位振幅，并产生局灶性癫痫样放电。这些作用可通过预先应用白细胞介素-1受体拮抗剂来预防。我们的研究结果表明，先天免疫反应可能参与急性癫痫发作，增加神经元的兴奋性，通过释放白细胞介素-1响应TLR 4检测与感染的中枢神经系统和脑损伤的危险信号。这些结果表明先天免疫在癫痫发生中的重要作用，并通过药理学阻断TLR 4和活化胶质细胞释放的促炎介质，在人类癫痫发作疾病的研究和治疗中关注胶质细胞抑制。
Brain glial cells, five times more prevalent than neurons, have recently received attention for their potential involvement in epileptic seizures. Microglia and astrocytes, associated with inflammatory innate immune responses, are responsible for surveillance of brain damage that frequently results in seizures. Thus, an intriguing suggestion has been put forward that seizures may be facilitated and perhaps triggered by brain immune responses. Indeed, recent evidence strongly implicates innate immune responses in lowering seizure threshold in experimental models of epilepsy, yet, there is no proof that they can play an independent role in initiating seizures in vivo. Here, we show that cortical innate immune responses alone produce profound increases of brain excitability resulting in focal seizures. We found that cortical application of lipopolysaccharide, binding to toll-like receptor 4 (TLR4), triples evoked field potential amplitudes and produces focal epileptiform discharges. These effects are prevented by pre-application of interleukin-1 receptor antagonist. Our results demonstrate how the innate immune response may participate in acute seizures, increasing neuronal excitability through interleukin-1 release in response to TLR4 detection of the danger signals associated with infections of the central nervous system and with brain injury. These results suggest an important role of innate immunity in epileptogenesis and focus on glial inhibition, through pharmacological blockade of TLR4 and the pro-inflammatory mediators released by activated glia, in the study and treatment of seizure disorders in humans.