Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation.
Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation.
复制标题
DOI：
10.1038/tp.2016.200
复制
发表时间：
2016-10-18
影响因子：
6.8
通讯作者：
O'Connor JC
中科院分区：
文献类型：
--
作者：
Parrott JM;Redus L;Santana-Coelho D;Morales J;Gao X;O'Connor JC
色氨酸代谢的犬尿氨酸途径在介导炎症的行为效应中起着重要作用，这对于了解神经精神共病和开发新的治疗方法具有重要意义。抑制限速酶，吲哚胺2，3-双加氧酶(IDO)，可以防止许多这些炎症诱导的临床前行为的发展。然而，下游代谢平衡失调，即产生神经活性犬尿氨酸的地方，被认为是炎症诱导抑郁的一个重要的功能致病特征。在这里，我们利用两个新的转基因小鼠品系来直接测试这一假设，即神经毒性犬尿氨酸代谢在外周免疫激活后会导致抑郁样行为。野生型(WT)或犬尿氨酸-3-单加氧酶(KMO)缺陷(KMO-−/−)小鼠腹腔注射脂多糖(LPS0.5 mg kg−1)或生理盐水。在免疫攻击后24 小时，测量多个区域的抑郁样行为。脂多糖可诱导出强健的抑郁样表型，但kmo−/−小鼠在尾部悬吊试验中不受脂多糖诱导的不动，并减少Y迷宫中的自发改变。直接给予KMO的代谢产物3-羟基犬尿氨酸，可引起抑郁样行为的剂量依赖性增加。靶向缺失3-羟基邻氨基苯甲酸双加氧酶(HAAO)的小鼠，产生喹啉酸的酶，也同样受到内毒素的挑战。与kmo−/−小鼠相似，内毒素在TST过程中不能增加小鼠的不动能力。虽然犬尿氨酸代谢通常在行为显著的脑区增加，但在背侧海马区发生了明显的向依赖于KMO的犬尿氨酸代谢转变，以响应内毒素。综上所述，这些结果表明，KMO是外周内毒素刺激诱导的海马区依赖的抑郁样行为的关键介质。
The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO−/−) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg−1) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO−/− mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO−/− mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO-dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge.