Tumor necrosis factor-α inhibits seizures in mice via p75 receptors
Tumor necrosis factor-α inhibits seizures in mice via p75 receptors
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DOI：
10.1002/ana.20480
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发表时间：
2005-06-01
影响因子：
11.2
通讯作者：
Vezzani, A
中科院分区：
文献类型：
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作者：
Balosso, S;Ravizza, T;Vezzani, A
脑炎症反应已被描述在各种神经系统疾病，包括癫痫。虽然有明确的证据表明，细胞因子影响神经胶质细胞的功能和血脑屏障的通透性，稀缺的信息是可用的癫痫发作的脑炎症的功能后果。我们研究了肿瘤坏死因子-α（TNF）-α及其p55和p75受体在癫痫发作调制中的作用。我们发现，海马内注射鼠重组TNF-α有效地抑制小鼠癫痫发作，而对小鼠p55受体表现出强特异性的人重组TNF-α则无效。在小鼠海马神经元中检测到p75受体，而p55受体不存在。TNF-α系统受到干扰的转基因小鼠在癫痫发作易感性方面表现出深刻的改变：星形胶质细胞TNF-α过表达与癫痫发作减少相关，而缺乏TNF-α p75或p55和p75受体的小鼠癫痫发作时间延长。p55受体缺陷的小鼠仅表现出癫痫发作减少;并且p75和TNF受体相关因子2蛋白水平在其脑内均上调。我们的研究结果表明，脑内TNF-α水平的增加导致小鼠癫痫发作的显着抑制，这种作用是由神经元p75受体介导的。这一证据突出了TNF-α在大脑中的新功能，并表明了一种新的抗惊厥干预系统。
Brain inflammatory reactions have been described in various neurological disorders, including epilepsy. Although there is clear evidence that cytokines affect neuroglial functions and blood-brain barrier permeability, scarce information is available on the functional consequences of brain inflammation on seizures. We studied the role of tumor necrosis factor-alpha (TNF)-alpha and its p55 and p75 receptors in seizure modulation. We found that intrahippocampal injection of murine recombinant TNF-alpha potently inhibits seizure in mice while human recombinant TNF-alpha, which shows strong specificity for mouse p55 receptors, was ineffective. p75 receptors were detected in mouse hippocampal neurons, whereas p55 receptors were absent. Transgenic mice with a perturbed TNF-alpha system showed profound alterations in seizure susceptibility: astrocytic overexpression of TNF-alpha was associated with reduced seizures, whereas mice lacking TNF-alpha p75 or both p55 and p75, receptors showed prolonged seizures. Mice deficient in p55 receptor only showed reduced seizures; and both p75 and TNF receptor-associated factor 2 protein levels were upregulated in their hippocampi. Our findings show that increased brain levels of TNF-alpha result in significant inhibition of seizures in mice, and this action is mediated by neuronal p75 receptors. This evidence highlights a novel function of TNF-alpha in brain and indicates a new system for anticonvulsive intervention.