Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE17177, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE17177, Sweden; Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm County Council, Karolinska Institutet & Stockholm Health Care Services, Karolinska University Hospital, Stockholm, Sweden.
Eur Neuropsychopharmacol. 2021 Feb;43:52-62. doi: 10.1016/j.euroneuro.2020.11.018. Epub 2020 Dec 16.
The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites such as kynurenic acid (KYNA), quinolinic acid (QUIN), and picolinic acid (PIC) thought to be involved in the pathophysiology of psychosis, major depression, and suicidal behavior. Here, we analyzed cerebrospinal fluid (CSF) concentrations of tryptophan, kynurenine, KYNA, QUIN, and PIC utilizing ultra-performance liquid chromatography - tandem mass spectrometry system (UPLC-MS/MS) in persons with bipolar disorder (n = 101) and healthy controls (n = 80) to investigate if the metabolites correlated with depressive symptoms or to the history of suicidal behavior. Furthermore, we analyzed if genetic variants of the enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) were associated with the CSF concentrations of PIC and QUIN. We found that CSF KYNA and PIC concentrations, as well as the kynurenine/tryptophan ratio were increased in bipolar disorder compared with controls. CSF PIC concentrations were lower in subjects with a history of suicidal behavior than those without, supporting the hypothesis that low CSF PIC is a marker of vulnerability for suicidality. Bipolar subjects taking antidepressants had higher CSF concentrations of kynurenine and KYNA than subjects not given these medications. A negative association was found between a genetic variant of ACMSD and the ratio of PIC/QUIN, indicating that a polymorphism in ACMSD is associated with excess of QUIN formation at the expense of PIC. The present results confirm that the kynurenine pathway is activated in bipolar disorder, and suggest that shifting the activity of the kynurenine pathway away from QUIN production towards a production of KYNA and PIC might be a beneficial therapeutic strategy.
色氨酸降解的犬尿酸途径产生几种神经活性代谢物，如犬尿酸（KYNA）、喹啉酸（QUIN）和吡啶酸（PIC），这些代谢物被认为与精神病、重度抑郁症和自杀行为的病理生理学有关。在这里，我们利用超高效液相色谱-串联质谱系统（UPLC-MS/MS）分析了双相情感障碍患者（n=101）和健康对照组（n=80）的脑脊液（CSF）中色氨酸、犬尿氨酸、KYNA、QUIN 和 PIC 的浓度，以研究这些代谢物是否与抑郁症状或自杀行为的历史相关。此外，我们还分析了酶氨基-β-羧基戊烯酸半醛脱羧酶（ACMSD）的遗传变异是否与 CSF 中 PIC 和 QUIN 的浓度相关。我们发现，与对照组相比，双相情感障碍患者的 CSF KYNA 和 PIC 浓度以及犬尿氨酸/色氨酸比值升高。有自杀行为史的受试者的 CSF PIC 浓度低于无自杀行为史的受试者，这支持了 CSF PIC 水平低是自杀易感性的标志物的假说。服用抗抑郁药的双相情感障碍患者的 CSF 犬尿氨酸和 KYNA 浓度高于未服用这些药物的患者。我们发现 ACMSD 的一个遗传变异与 PIC/QUIN 的比值呈负相关，这表明 ACMSD 的多态性与 QUIN 形成的增加而 PIC 的减少有关。目前的结果证实了犬尿酸途径在双相情感障碍中被激活，并表明将犬尿酸途径的活性从 QUIN 生成转移到 KYNA 和 PIC 的生成可能是一种有益的治疗策略。
