Indoleamine 2,3-dioxygenase 1 deletion promotes Theiler's virus-induced seizures in C57BL/6J mice.
Indoleamine 2,3-dioxygenase 1 deletion promotes Theiler's virus-induced seizures in C57BL/6J mice.
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DOI：
10.1111/epi.14675
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发表时间：
2019-04
期刊：
影响因子：
5.6
通讯作者：
Steelman AJ
中科院分区：
文献类型：
--
作者：
Juda MB;Brooks AK;Towers AE;Freund GG;McCusker RH;Steelman AJ
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) 由炎症细胞因子诱导，具有将色氨酸 (Trp) 代谢为犬尿氨酸 (Kyn) 的功能。犬尿氨酸可进一步代谢产生犬尿酸 (KynA) 和 N-甲基-D-天冬氨酸 (NMDA) 受体激动剂喹啉酸 (QuinA)。在本研究中，我们试图确定 Ido1 在病毒性脑炎动物模型中促进癫痫发作的作用。 C57BL/6J 和 Ido1 敲除小鼠 (Ido1-KO) 感染了泰勒氏鼠脑脊髓炎病毒 (TMEV)。使用定量 RT-PCR 评估海马促炎细胞因子、Ido1 和病毒 RNA 的表达。每天记录体重和癫痫评分。高架零迷宫用于评估行为差异，并通过免疫组织化学测定海马病理学。受感染的 C57BL/6J 小鼠在癫痫发作前上调促炎细胞因子、Ido1 和编码负责犬尿氨酸途径中 QuinA 产生的酶级联的基因。与 C57BL/6J 小鼠相比，Ido1-KO 小鼠的癫痫发作发生率升高。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。促炎细胞因子和病毒RNA的表达均不会因基因型而改变。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，Ido1 缺失会促进急性 TMEV 脑炎期间的癫痫发作和神经发病。
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 (Trp) to kynurenine (Kyn). Kynurenine can be further metabolized to produce kynurenic acid (KynA) and the N-methyl-D-aspartate (NMDA) 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 RT-PCR 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 upregulated 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.
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影响因子：
5.6
作者：
Aronica E;Bauer S;Bozzi Y;Caleo M;Dingledine R;Gorter JA;Henshall DC;Kaufer D;Koh S;Löscher W;Louboutin JP;Mishto M;Norwood BA;Palma E;Poulter MO;Terrone G;Vezzani A;Kaminski RM
通讯作者：
Kaminski RM
影响因子：
3.7
作者：
Choi, Su-Lim;Lee, Sang Jun;Lee, Seung-Goo
通讯作者：
Lee, Seung-Goo
影响因子：
3.7
作者：
George BP;Schneider EB;Venkatesan A
通讯作者：
Venkatesan A
影响因子：
15.3
作者：
Theiler, M;Gard, S
通讯作者：
Gard, S
影响因子：
2.4
作者：
Steelman, Andrew J.;Alford, Eric;Welsh, C. Jane R.
通讯作者：
Welsh, C. Jane R.