Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Acta Neuropsychiatr. 2020 Feb;32(1):43-53. doi: 10.1017/neu.2019.44. Epub 2019 Dec 20.
Sustained immune activation leads to cognitive dysfunctions, depression-, and anxiety-like behaviours in humans and rodents. It is modelled by administration of lipopolysaccharides (LPS) to induce expression of pro-inflammatory cytokines that then activate indoleamine 2,3 dioxygenase (IDO1), the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Here, we ask whether chronic IDO1 inhibition by 1-methyl-tryptophan (1-MT, added at 2 g/l in the drinking water) or chronic inhibition of tryptophan 2,3 dioxygenase (TDO2), another enzyme capable of converting tryptophan to kynurenine, by 680C91 (15 mg/kg per os), can rescue LPS-induced (0.83-mg/kg intraperitoneally) anxiety and cognitive deficits. We also investigate the acute effects of 680C91 on serotonergic, dopaminergic, and kynurenine pathway metabolites.
We examined LPS-induced deficits in trace fear conditioning and anxiety in the light-dark box and elevated plus maze (EPM) in group-housed C57Bl6/N mice. Kynurenine pathway metabolites and monoamine levels were measured via high-performance liquid chromatography.
Chronic blockade of IDO1 with 1-MT did not rescue cognitive deficits or abrogate the anxiogenic behaviour caused by LPS despite a decrease in the brain kynurenine:tryptophan ratio. However, 1-MT by itself demonstrated anxiolytic properties in the EPM. Acute and chronic inhibition of TDO2 elevated brain levels of tryptophan, while chronic inhibition of TDO2 was unsuccessful in rescuing cognitive deficits and abrogating the anxiety caused by LPS.
In line with previous studies, we show that LPS administration induces anxiety and cognitive dysfunctions in mice that however were not reversed by chronic blockade of IDO1 or TDO2 at the doses used.
持续的免疫激活会导致人类和啮齿动物出现认知功能障碍、抑郁和焦虑样行为。通过给予脂多糖（LPS）来模拟这种情况，以诱导促炎细胞因子的表达，然后激活吲哚胺 2,3 双加氧酶（IDO1），这是色氨酸代谢中犬尿氨酸途径的限速酶。在这里，我们询问慢性 IDO1 抑制是否能通过 1-甲基色氨酸（1-MT，在饮用水中添加 2 g/l）或另一种能够将色氨酸转化为犬尿氨酸的色氨酸 2,3 双加氧酶（TDO2）的慢性抑制来挽救 LPS 诱导的（腹腔内 0.83mg/kg）焦虑和认知缺陷。我们还研究了 680C91 对 5-羟色胺能、多巴胺能和犬尿氨酸途径代谢物的急性影响。
我们在群居的 C57Bl6/N 小鼠中检查了 LPS 诱导的痕迹恐惧条件反射和明暗箱和高架十字迷宫（EPM）中的焦虑缺陷。通过高效液相色谱法测量犬尿氨酸途径代谢物和单胺水平。
尽管脑犬尿氨酸：色氨酸比值降低，但慢性 IDO1 阻断剂 1-MT 并不能挽救认知缺陷或消除 LPS 引起的焦虑行为。然而，1-MT 本身在 EPM 中表现出抗焦虑特性。TDO2 的急性和慢性抑制会升高大脑中的色氨酸水平，而慢性抑制 TDO2 未能挽救 LPS 引起的认知缺陷和焦虑。
与之前的研究一致，我们表明 LPS 给药会在小鼠中引起焦虑和认知功能障碍，但在使用的剂量下，慢性 IDO1 或 TDO2 阻断均未逆转这些障碍。
