Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Exp Neurol. 2013 Sep;247:429-37. doi: 10.1016/j.expneurol.2013.01.011. Epub 2013 Jan 16.
Resected epileptic tissues exhibit elements of chronic neuroinflammation that include elevated TNFα and increased TNFα receptor activation, but the seizure related consequences of chronic TNFα expression remain unknown. Twenty four hours after acute limbic seizures the rat hippocampus exhibited a rapid upregulation of TNFR1, but a simultaneous downregulation of TNFR2. These limbic seizures also evoked significant increases in measures of neuroinflammation and caused significant neuronal cell death in both the hilus and CA3 of the hippocampus. In order to mimic a state of chronic TNFα exposure, adeno-associated viral vectors were packaged with a TNF receptor 1 (TNFR1) specific agonist, human TNFα, or a TNF receptor 1/2 agonist, rat TNFα. Subsequently, chronic hippocampal overexpression of either TNFR ligand caused microglial activation and blood-brain barrier compromise, a pattern similar to limbic seizure-induced neuroinflammation. However, no evidence was found for neuronal cell death or spontaneous seizure activity. Thus, chronic, in vivo TNFα expression and the subsequent neuroinflammation alone did not cause cell death or elicit seizure activity. In contrast, chronic hippocampal activation of TNFR1 alone significantly increased limbic seizure sensitivity in both amygdala kainic acid and electrical amygdala kindling models, while chronic activation of both TNFR1 and TNFR2 significantly attenuated the amygdala kindling rate. With regard to endogenous TNFα, chronic hippocampal expression of a TNFα decoy receptor significantly reduced seizure-induced cell death in the hippocampus, but did not alter seizure susceptibility. These findings suggest that blockade of endogenous TNFα could attenuate seizure related neuropathology, while selective activation of TNFR2 could exert beneficial therapeutic effects on in vivo seizure sensitivity.
切除的癫痫组织表现出慢性神经炎症的特征，包括 TNFα 升高和 TNFα 受体激活增加，但慢性 TNFα 表达与癫痫相关的后果仍不清楚。急性边缘性癫痫发作 24 小时后，大鼠海马体迅速上调了 TNFR1，但同时下调了 TNFR2。这些边缘性癫痫发作还引起了神经炎症的显著增加，并导致海马体的齿状回和 CA3 区出现明显的神经元细胞死亡。为了模拟慢性 TNFα 暴露的状态，腺相关病毒载体被包装成 TNF 受体 1（TNFR1）特异性激动剂，人 TNFα，或 TNF 受体 1/2 激动剂，大鼠 TNFα。随后，慢性海马体过度表达任何一种 TNFR 配体都会导致小胶质细胞激活和血脑屏障破坏，这种模式类似于边缘性癫痫引起的神经炎症。然而，没有发现神经元细胞死亡或自发性癫痫活动的证据。因此，慢性、体内 TNFα 表达和随后的神经炎症本身不会导致细胞死亡或引发癫痫活动。相反，单独慢性海马体 TNFR1 的激活显著增加了杏仁核红藻氨酸和电杏仁核点燃模型中边缘性癫痫的敏感性，而 TNFR1 和 TNFR2 的慢性激活显著降低了杏仁核点燃的速度。至于内源性 TNFα，慢性海马体表达 TNFα 诱饵受体显著减少了海马体癫痫诱导的细胞死亡，但没有改变癫痫易感性。这些发现表明，阻断内源性 TNFα 可以减轻与癫痫相关的神经病理学，而选择性激活 TNFR2 可能对体内癫痫敏感性产生有益的治疗作用。
