The Role of Indoleamine 2,3-Dioxygenase in a Mouse Model of Neuroinflammation-Induced Depression
The Role of Indoleamine 2,3-Dioxygenase in a Mouse Model of Neuroinflammation-Induced Depression
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DOI：
10.3233/jad-2011-111097
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Eisel, Ulrich L. M.
中科院分区：
文献类型：
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作者：
Dobos, Nikoletta;de Vries, Erik F. J.;Eisel, Ulrich L. M.
吲哚胺2，3-双加氧酶(IDO)是一种由促炎细胞因子激活的酶，已被认为是神经退行性疾病(如阿尔茨海默病)和抑郁之间的潜在联系。本研究旨在确定神经炎症诱导的哺乳动物大脑中IDO水平的增加是否会导致抑郁样行为。通过单次脑室注射脂多糖(LPS)诱导小鼠神经炎症。分别于注射后第1、2、3、4天用小动物正电子发射断层扫描(PET)监测脑组织炎症反应，采用炎症标志物[C-11]-PK11195。在有或没有系统应用1-甲基-色氨酸(1-MT)的情况下，我们评估了抑郁样行为症状的发展与IDO的表达和活性的平行关系。在注射脂多糖后第3天，PK11195的PET信号达到一个非常显著的峰值，而在强迫游泳实验中，这些动物表现出明显的抑郁样行为，与车辆注射的动物相比。与这些发现相平行的是，脑干中IDO显著增加，血清中犬尿氨酸/色氨酸比率增加。此外，我们在这里首次报道，在实验条件下，1-MT抑制中枢诱导的神经炎症中的IDO可以防止抑郁样行为的发展。
Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases (like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS). Cerebral inflammation was monitored 1, 2, 3 and 4 days after the injection with small-animal positron emission tomography (PET) using the inflammatory marker [C-11]-PK11195. In the presence or absence of systemically applied 1-methyl-tryptophan (1-MT), a competitive IDO-inhibitor, we assessed the development of depressive-like behavioral symptoms in parallel with IDO expression and activity. The PK11195 PET signal reached a highly significant peak 3 days after LPS injection, while these animals displayed a significant increase of depressive-like behavior in the forced swim test compared to vehicle-injected animals. These findings were paralleled by a significant increase of IDO in the brainstem, and an increased kynurenine/tryptophan ratio in the serum. Moreover, we report here for the first time, that inhibition of IDO by 1-MT in centrally induced neuroinflammation under experimental conditions can prevent the development of depressive-like behavior.