Journal Article

An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation

Brundin, P, Guillemin, G J, Postolache, T T, Brundin, L, Lim, C K, Traskman-Bendz, L, Sellgren, C M, Samuelsson, M, Landén, M, Fuchs, D, Pålsson, E, Erhardt, S, Lundgren, K, Grit, J

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/477/2811 / 692/53/2423 / 692/699/476/1333 / 692/699/476/1414 / Adolescent / Adult / Aged / Alleles / assessment scale / Behavioral Sciences / Biological Psychology / Carboxy-Lyases - genetics / Case-Control Studies / Child / chromium picolinate / Clinical Medicine / controlled-trial / epsilon-semialdehyde decarboxylase / Female / high-protein diet / Humans / Inflammation / Klinisk medicin / Kynurenine - metabolism / major depressive disorder / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Medicine / Medicine & Public Health / Middle Aged / Neurosciences / Original / original-article / Pharmacotherapy / Picolinic Acids - blood / Picolinic Acids - cerebrospinal fluid / picolinic-acid / Polymorphism, Single Nucleotide / Psychiatry / Psykiatri / quinolinic acid / Quinolinic Acid - blood / Quinolinic Acid - cerebrospinal fluid / rat / Self-Injurious Behavior - blood / Self-Injurious Behavior - cerebrospinal fluid / Self-Injurious Behavior - genetics / Suicidal behavior / Suicidal Ideation / Suicide, Attempted / tryptophan / Young Adult