Brundin L, Sellgren C M, Lim C K, Grit J, Pålsson E, Landén M, Samuelsson M, Lundgren K, Brundin P, Fuchs D, Postolache T T, Traskman-Bendz L, Guillemin G J, Erhardt S
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Transl Psychiatry. 2016 Aug 2;6(8):e865. doi: 10.1038/tp.2016.133.
Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.
新出现的证据表明，炎症在抑郁症和自杀行为中起关键作用。犬尿氨酸途径参与神经炎症并调节谷氨酸神经传递。在自杀患者的脑脊液（CSF）中，炎症细胞因子和犬尿氨酸代谢产物喹啉酸（QUIN，一种N-甲基-D-天冬氨酸受体激动剂）的水平会升高。氨基-β-羧基粘康酸半醛脱羧酶（ACMSD）通过竞争性产生神经保护代谢产物吡啶甲酸（PIC）来限制QUIN的形成。因此，ACMSD活性降低会导致QUIN过量。我们检验了ACMSD活性不足是自杀行为基础这一假设。我们测量了137名有自杀行为的患者和71名健康对照者的脑脊液和血浆样本中的PIC和QUIN。我们使用《精神疾病诊断与统计手册》第四版（DSM-IV）、蒙哥马利-Åsberg抑郁评定量表和自杀评估量表来评估行为变化。最后，我们对77名患者和150名基于人群的对照者的ACMSD标签单核苷酸多态性（SNP）进行了基因分型。自杀未遂者的脑脊液（P<0.001）和血液（分别为P=0.001和P<0.01）中的PIC均降低，PIC/QUIN比值也降低。根据重复测量结果，自杀未遂后2年内脑脊液中的PIC持续降低。ACMSD SNP rs2121337的次要C等位基因在自杀未遂者中更为普遍，且与脑脊液中QUIN增加有关。综合来看，我们的数据表明，自杀者中QUIN水平升高可能是由于ACMSD活性降低所致。我们得出结论，犬尿氨酸代谢产物的测量可作为自杀风险的生物标志物进行探索，并且ACMSD是自杀行为的一个潜在治疗靶点。
