Laboratory of Neuroimmunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Neural Regulation of Cancer Laboratory, Drug Discovery Biology, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Mol Psychiatry. 2019 Oct;24(10):1523-1532. doi: 10.1038/s41380-018-0076-7. Epub 2018 Jul 9.
Inflammation activates indoleamine 2,3-dioxygenase (IDO) which metabolizes tryptophan into kynurenine. Circulating kynurenine is transported into the brain by the large amino transporter LAT1 at the level of the blood-brain barrier. We hypothesized that administration of leucine that has a high affinity for LAT1 should prevent the entry of kynurenine into the brain and attenuate the formation of neurotoxic kynurenine metabolites. To test whether leucine could prevent inflammation-induced depression-like behavior, mice were treated with lipopolysaccharide (LPS, 0.83 mg/kg IP) or saline and treated with L-leucine (50 mg/kg, IP) or vehicle administered before and 6 h after LPS. Depression-like behavior was measured by increased duration of immobility in the forced swim test and decreased sucrose preference. Leucine decreased brain kynurenine levels, blocked LPS-induced depression-like behavior and had antidepressant-like effects in control mice. Leucine had no effect of its own on sickness behavior and neuroinflammation. To confirm that leucine acts by interfering with the transport of kynurenine into the brain, mice were injected with L-leucine (300 mg/kg, IP) immediately before kynurenine (33 mg/kg IP) and brain kynurenine and depression-like behavior were measured 3 h later. Leucine did prevent the entry of exogenous kynurenine into the brain and abrogated depression-like behavior measured by increased duration of immobility in the forced swim test. Additional experiments using an in vitro model of the blood-brain barrier confirmed that kynurenine competes with leucine at the level of the amino acid transporter LAT1 for brain uptake. These experiments also revealed that efflux was the dominant direction of kynurenine transport and was largely independent of LAT1 and leucine, which explains why leucine could block brain uptake of kynurenine without affecting brain clearance. These findings demonstrate that leucine has antidepressant properties vis-à-vis inflammation-induced depression and one mechanism for this is by blocking the ability of kynurenine to enter the brain.
炎症激活吲哚胺 2,3-双加氧酶（IDO），该酶将色氨酸代谢为犬尿氨酸。循环中的犬尿氨酸通过血脑屏障处的大型氨基酸转运体 LAT1 转运到大脑中。我们假设，具有高亲和力的亮氨酸的给药应该可以防止犬尿氨酸进入大脑，并减轻神经毒性犬尿氨酸代谢物的形成。为了测试亮氨酸是否可以预防炎症引起的抑郁样行为，将小鼠用脂多糖（LPS，0.83mg/kg IP）或生理盐水处理，并在 LPS 前和 6 小时后用 L-亮氨酸（50mg/kg，IP）或载体处理。通过强迫游泳试验中不动时间的延长和蔗糖偏好的降低来测量抑郁样行为。亮氨酸降低了脑犬尿氨酸水平，阻断了 LPS 诱导的抑郁样行为，并在对照小鼠中具有抗抑郁作用。亮氨酸本身对疾病行为和神经炎症没有影响。为了确认亮氨酸通过干扰犬尿氨酸进入大脑的转运起作用，将小鼠用 L-亮氨酸（300mg/kg，IP）立即在犬尿氨酸（33mg/kg IP）之前注射，并在 3 小时后测量脑犬尿氨酸和抑郁样行为。亮氨酸确实阻止了外源性犬尿氨酸进入大脑，并通过增加强迫游泳试验中的不动时间来消除抑郁样行为。使用血脑屏障的体外模型进行的其他实验证实，犬尿氨酸在氨基酸转运体 LAT1 水平上与亮氨酸竞争进入大脑。这些实验还表明，外排是犬尿氨酸转运的主导方向，并且在很大程度上独立于 LAT1 和亮氨酸，这解释了为什么亮氨酸可以阻止犬尿氨酸进入大脑而不影响脑清除率。这些发现表明，亮氨酸具有针对炎症引起的抑郁的抗抑郁特性，其机制之一是阻止犬尿氨酸进入大脑的能力。
