Mouri Akihiro, Hasegawa Masaya, Kunisawa Kazuo, Saito Kuniaki, Nabeshima Toshitaka
Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Sciences.
Japanese Drug Organization of Appropriate Use and Research.
Nihon Yakurigaku Zasshi. 2023 May 1;158(3):233-237. doi: 10.1254/fpj.22139. Epub 2023 Mar 29.
The monoamine hypothesis has been common hypotheses for the pathophysiology of major depressive disorder (MDD). Since mainstream antidepressants are selective serotonin (5-HT) reuptake inhibitors, hypo-serotonergic function has been implicated in the MDD. However, one-third of patients are refractory to the treatment with antidepressants. Tryptophan (TRP) is metabolized via the kynurenine (KYN) and 5-HT pathways. Indoleamine 2,3-dioxygenase 1 (IDO1) is the first metabolizing enzyme in the TRP-KYN pathway which is inducible by pro-inflammatory cytokines, involved depression-like behavior via 5-HT depletion due to decreased level of TRP in the 5-HT pathway. Kynurenine 3-monooxygenase (KMO) is the enzyme in the metabolism of KYN to 3-hydroxykynurenine. KMO deficiency increases level of kynurenic acid (KA), a KYN metabolite by kynurenine aminotransferases (KATs) and induces depression-like behavior. Interestingly, Chronic unpredictable mild stress (CUMS) is associated with a disruption of the hypothalamus-pituitary-adrenocortical (HPA) system and increases KA level with decreased KMO expression in the prefrontal cortex. The decrease of KMO may be related to the reduction in expression of microglia, since KMO is mainly found in microglia in the nervous system. CUMS increases KA level via alternation of enzymes from KMO to KAT. KA is α7 nicotinic acetylcholine receptor (α7nAChR) antagonist. Activation of α7nAChR by nicotine or galantamine attenuates CUMS-induced depression-like behaviors. Taken together, depletion of 5-HT by induction of IDO1 and α7nAChR antagonism by KA via decreased KMO expression cause depression-like behavior, suggesting that metabolic alterations in TRP-KYN pathway are highly involved in the pathophysiology of MDD. Therefore, TRP-KYN pathway is expected to be an attractive target for the development of novel diagnosis of MDD and antidepressants.
单胺假说是重度抑郁症（MDD）病理生理学的常见假说。由于主流抗抑郁药是选择性5-羟色胺（5-HT）再摄取抑制剂，血清素功能低下与MDD有关。然而，三分之一的患者对抗抑郁药治疗无效。色氨酸（TRP）通过犬尿氨酸（KYN）和5-HT途径代谢。吲哚胺2,3-双加氧酶1（IDO1）是TRP-KYN途径中的第一种代谢酶，可被促炎细胞因子诱导，通过5-HT途径中TRP水平降低导致5-HT耗竭而引发类似抑郁的行为。犬尿氨酸3-单加氧酶（KMO）是KYN代谢为3-羟基犬尿氨酸的酶。KMO缺乏会增加犬尿喹啉酸（KA）的水平，KA是犬尿氨酸转氨酶（KATs）产生的KYN代谢产物，并引发类似抑郁的行为。有趣的是，慢性不可预测轻度应激（CUMS）与下丘脑-垂体-肾上腺皮质（HPA）系统紊乱有关，并增加KA水平，同时前额叶皮质中KMO表达降低。KMO的降低可能与小胶质细胞表达减少有关，因为KMO主要存在于神经系统的小胶质细胞中。CUMS通过将酶从KMO转变为KAT来增加KA水平。KA是α7烟碱型乙酰胆碱受体（α7nAChR）拮抗剂。尼古丁或加兰他敏激活α7nAChR可减轻CUMS诱导的类似抑郁行为。综上所述，IDO1诱导导致5-HT耗竭以及KA通过降低KMO表达产生α7nAChR拮抗作用会引发类似抑郁行为，这表明TRP-KYN途径中的代谢改变与MDD病理生理学密切相关。因此，TRP-KYN途径有望成为开发MDD新型诊断方法和抗抑郁药的有吸引力靶点。
