Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice
Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice
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DOI：
10.1038/sj.mp.4002148
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发表时间：
2009-05-01
影响因子：
11
通讯作者：
Dantzer, R.
中科院分区：
文献类型：
--
作者：
O'Connor, J. C.;Lawson, M. A.;Dantzer, R.
尽管已经提出了在炎症性疾病中升高的色氨酸降解酶吲哚胺2，3-双加氧酶（IDO）的活性介导共病抑郁，但其致病作用从未被测试。我们报告说，外周给药的脂多糖（LPS）激活IDO和高潮在一个独特的抑郁样行为综合征，增加不动的持续时间在强迫游泳和尾部悬挂测试测量。用抗炎四环素衍生物米诺环素间接阻断IDO活化，其减弱LPS诱导的促炎细胞因子的表达，或直接用IDO拮抗剂1-甲基色氨酸（1-MT）阻断IDO活化，防止抑郁样行为的发展。米诺环素和1-MT均使LPS处理小鼠的血浆和脑中的犬尿氨酸/色氨酸比率正常化，而不改变LPS诱导的脑5-羟色胺周转增加。将L-犬尿氨酸（由IDO产生的色氨酸的代谢物）给予未处理小鼠剂量依赖性地诱导抑郁样行为。这些结果暗示IDO作为炎症诱导的抑郁样行为的关键分子介质，可能通过沿着犬尿氨酸途径沿着色氨酸的催化。
Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.