Department of Animal Sciences, College of Agricultural, Consumer, and Environmental Sciences, Urbana, Illinois.
Neuroscience Program, College of Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois.
Epilepsia. 2019 Apr;60(4):626-635. doi: 10.1111/epi.14675. Epub 2019 Feb 15.
Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3-dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N-methyl-d-aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis.
C57BL/6J and Ido1 knockout mice (Ido1-KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real-time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry.
Infected C57BL/6J mice up-regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1-KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1-KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1-KO mice.
Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.
病毒性脑炎会增加癫痫发作和癫痫的风险。吲哚胺 2,3-双加氧酶 1（Ido1）可被炎症细胞因子诱导，其功能是将色氨酸代谢为犬尿氨酸。犬尿氨酸可进一步代谢为犬尿喹啉酸和 N-甲基-D-天冬氨酸受体激动剂喹啉酸（QuinA）。在本研究中，我们试图确定 Ido1 在促进病毒性脑炎动物模型中癫痫发作中的作用。
C57BL/6J 和 Ido1 敲除（Ido1-KO）小鼠感染 Theiler's 鼠脑脊髓炎病毒（TMEV）。实时定量聚合酶链反应用于评估海马炎症细胞因子、Ido1 和病毒 RNA 的表达。每日记录体重和癫痫发作评分。高架十字迷宫用于评估行为差异，免疫组织化学用于检测海马病理学。
在癫痫发作之前，感染的 C57BL/6J 小鼠上调了促炎细胞因子、Ido1 以及编码犬尿氨酸途径中 QuinA 产生的酶级联反应的基因。与 C57BL/6J 小鼠相比，Ido1-KO 小鼠的癫痫发作发生率更高。与 C57BL/6J 小鼠相比，感染增加了 Ido1-KO 小鼠的运动活性。此外，癫痫发作的发生与过度兴奋有关。基因型并未改变促炎细胞因子的表达或病毒 RNA。免疫组织化学分析显示 Ido1-KO 小鼠海马病理学增加。
我们的研究结果表明，在急性 TMEV 脑炎期间，Ido1 缺失会促进癫痫发作和神经病变。
