Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis
Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis
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DOI：
10.1046/j.1528-1157.43.s.5.14.x
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发表时间：
2002-01-01
期刊：
影响因子：
5.6
通讯作者：
De Simoni, MG
中科院分区：
文献类型：
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作者：
Vezzani, A;Moneta, D;De Simoni, MG
目的：我们研究了诱导边缘癫痫发作后啮齿动物海马中促炎细胞因子和相关分子表达的变化。然后，我们研究了药物干预对白细胞介素（IL）-1系统对边缘癫痫发作和癫痫发作的转基因小鼠过表达的天然存在的拮抗剂IL-1（IL-1 Ra）在astrocytes.Methods：边缘癫痫发作的诱导啮齿动物海马内注射海人酸或荷包牡丹碱甲碘化物或电刺激海马引起癫痫持续状态（SE）。根据Racine's量表，通过EEG分析和行为观察记录癫痫活动。在海马细胞因子的表达进行了研究，通过逆转录-聚合酶链反应（RT-PCR），然后Southern印迹定量的各种信使RNA（mRNA）和免疫cytochemistics.Results：我们发现，边缘癫痫发作迅速和短暂增强IL-1 β，IL-6，和肿瘤坏死因子（TNF）-α mRNA在海马SE后6小时的峰值效应。各种细胞因子的免疫反应性在胶质细胞中增加。IL-1 Ra的升高在SE后24 h达到高峰，因此IL-1 Ra的升高延迟。此外，1 L-1 Ra并不像外周炎症那样大量过量产生，而是与IL-1 β的摩尔比为1：1。海马内注射IL-1 β使癫痫发作活动恶化，而IL-1 Ra在各种边缘癫痫发作模型中是一种强有力的抗惊厥药。转基因小鼠过度表达IL-1 Ra的星形胶质细胞不太敏感荷包牡丹碱诱导的seizure.Conclusions：这项研究表明，边缘癫痫发作在啮齿类动物迅速和可逆地诱导促炎细胞因子在胶质细胞，并建议在脑中的IL-1 Ra/IL-1 β比例的变化可能代表一个有效的生理病理机制，以控制癫痫发作。
Purpose: We investigated the changes in the expression of proinflammatory cytokines and related molecules in the rodent hippocampus after the induction of limbic seizures. We then studied the effects of pharmacologic intervention on the interleukin (IL)-1 system on limbic seizures and the susceptibility to seizures of transgenic mice overexpressing the naturally occurring antagonist of IL-1 (IL-1Ra) in astrocytes.Methods: Limbic seizures were induced in rodents by intra-hippocampal injection of kainic acid or bicuculline methiodide or by electrical stimulation of the hippocampus causing status epilepticus (SE). Seizure activity was recorded by EEG analysis and behavioral observation according to Racine's scale. Cytokine expression in the hippocampus was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by Southern blot quantification of the various messenger RNAs (mRNAs) and by immunocytochemistry.Results: We found that limbic seizures rapidly and transiently enhanced IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha mRNA in the hippocampus with a peak effect at 6 h after SE. Immunoreactivity of the various cytokines was increased in glia. The increase of IL-1Ra was delayed because the peak effect was observed at 24 h after SE. Moreover, 1L-1Ra was not produced in large excess, as during peripheral inflammation but in a molar ratio to IL-1beta of 1:1. Intrahippocampal injection of IL-1beta worsened seizure activity, whereas IL-1Ra was a powerful anticonvulsant in various models of limbic seizures. Transgenic mice overexpressing IL-1Ra in astrocytes were less sensitive to bicuculline-induced seizures.Conclusions: This study shows that limbic seizures in rodents rapidly and reversibly induce proinflammatory cytokines in glia and suggests that changes in the IL-1Ra/IL-1beta ratio in brain may represent an effective physiopathologic mechanism to control seizures.