Indoleamine-2,3-Dioxygenase 1 Deficiency Suppresses Seizures in Epilepsy.
Indoleamine-2,3-Dioxygenase 1 Deficiency Suppresses Seizures in Epilepsy.
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吲哚胺-2,3-双加氧酶 1 缺乏症可抑制癫痫发作
DOI：
10.3389/fncel.2021.638854
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发表时间：
2021
影响因子：
5.3
通讯作者：
Xie W
中科院分区：
文献类型：
--
作者：
Deng N;Hu J;Hong Y;Ding Y;Xiong Y;Wu Z;Xie W
背景：吲哚胺-2，3-双加氧酶1（IDO 1）是色氨酸（TRP）代谢为犬尿氨酸（KYN）的起始酶和限速酶。IDO 1依赖性神经毒性KYN代谢在许多神经退行性疾病的发病机制中起着至关重要的作用。然而，IDO 1在癫痫中的作用尚不清楚。目的：在本研究中，我们研究IDO 1缺乏是否会影响锂-匹罗卡品诱导的癫痫模型。方法：癫痫患者和对照组。对雄性C57 BL/6小鼠和IDO 1敲除（KO，IDO 1-/-）小鼠进行锂和毛果芸香碱的腹膜内注射以诱导癫痫。采用酶联免疫吸附试验（ELISA）和液相色谱-质谱联用（LC-MS）分别检测癫痫患者和癫痫小鼠体内IDO 1水平、TRP和KYN浓度。然后，在锂-匹罗卡品诱导癫痫的KO和野生型（WT）小鼠之间比较与癫痫发作和神经元损伤相关的行为表型。为了探索IDO 1缺乏的影响中涉及的潜在途径，通过LC-MS、免疫组织化学和ELISA测量犬尿烯酸（KYNA）和喹啉酸（QUIN）的浓度、胶质细胞活化、主要促炎细胞因子的水平和抗氧化酶活性。结果：癫痫患者血清和脑脊液中IDO 1水平及KYN/TRP比值均升高。此外，IDO 1水平，KYN/TRP比率，和促炎细胞因子的水平在血清和脑内癫痫持续状态（SE）后的急性期和慢性期的小鼠增加。IDO 1定位于癫痫小鼠的小胶质细胞。IDO 1缺乏延迟SE发作，并减弱自发性复发性癫痫发作（SRS）的频率、持续时间和严重程度。此外，IDO 1缺乏改善神经元存活。此外，IDO 1 −/−癫痫小鼠表现出QUIN产生、神经胶质细胞活化和促炎细胞因子水平的逐渐下降，以及抗氧化酶活性的增强。结论：IDO 1缺失通过减少IDO 1依赖的神经毒性代谢产物的产生来抑制癫痫发作并减轻神经元损伤，这最终抑制了胶质细胞活化和促炎细胞因子的产生并提高了抗氧化酶活性。我们的研究表明IDO 1可能参与癫痫的发病机制，并有可能成为癫痫治疗的一个治疗靶点。
Background: Indoleamine-2,3-dioxygenase 1 (IDO1) is the initial and rate-limiting enzyme in the metabolism of tryptophan (TRP) to kynurenine (KYN). IDO1-dependent neurotoxic KYN metabolism plays a crucial role in the pathogenesis of many neurodegenerative disorders. However, the function of IDO1 in epilepsy is still unclear. Objective: In this study, we investigated whether IDO1 deficiency could affect epilepsy in a lithium-pilocarpine-induced model. Methods: Patients with epilepsy and controls were enrolled. Male C57BL/6 mice and IDO1 knockout (KO, IDO1−/−) mice were subjected to intraperitoneal injection of lithium and pilocarpine to induce epilepsy. The levels of IDO1 and concentrations of TRP and KYN in patients with epilepsy and epileptic mice were evaluated by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry (LC-MS), respectively. Then, behavioral phenotypes related to epileptic seizures and neuronal damage were compared between KO and wild-type (WT) mice with lithium-pilocarpine-induced epilepsy. To explore the underlying pathways involved in the effects of IDO1 deficiency, the concentrations of kynurenic acid (KYNA) and quinolinic acid (QUIN), glial cell activation, the levels of major pro-inflammatory cytokines, and antioxidant enzyme activity were measured by LC-MS, immunohistochemistry, and ELISA. Results: In this study, IDO1 levels and the KYN/TRP ratio in the sera and cerebrospinal fluid (CSF) were increased in patients with epilepsy. Also, IDO1 levels, the KYN/TRP ratio, and the levels of pro-inflammatory cytokines in the sera and hippocampi were increased in mice during the acute phase and chronic phase after status epilepticus (SE). Furthermore, IDO1 was localized in microglial cells in epileptic mice. IDO1 deficiency delayed SE onset and attenuated the frequency, duration, and severity of spontaneous recurrent seizures (SRSs). Moreover, IDO1 deficiency improved neuronal survival. Additionally, IDO1−/− epileptic mice showed progressive declines in QUIN production, glial cell activation and pro-inflammatory cytokines levels, and enhanced antioxidant enzyme activity. Conclusions: IDO1 deletion suppressed seizures and alleviated neuronal damage by reducing the IDO1-dependent production of neurotoxic metabolites, which finally inhibited glial cell activation and pro-inflammatory cytokine production and improved antioxidant enzyme activity. Our study demonstrates that IDO1 may be involved in the pathogenesis of epilepsy and has the potential to be a therapeutic target for epilepsy treatment.
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