Sex- and suicide-specific alterations in the kynurenine pathway in the anterior cingulate cortex in major depression.

Autor: Brown SJ; School of Medical, Indigenous and Health Sciences and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia. Samara@uow.edu.au., Christofides K; NICM Health Research Institute, Western Sydney University, Westmead, NSW, Australia., Weissleder C; Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia.; Mechanism and Therapy of Genetic Brain Diseases, Institut Imagine, Paris, France., Huang XF; School of Medical, Indigenous and Health Sciences and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia., Shannon Weickert C; Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia.; Department of Neuroscience & Physiology, Upstate Medical University, Syracuse, NY, USA.; Discipline of Psychiatry and Mental Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia., Lim CK; Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, Australia.; Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia., Newell KA; School of Medical, Indigenous and Health Sciences and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia. knewell@uow.edu.au.
Jazyk: angličtina
Zdroj: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2024 Feb; Vol. 49 (3), pp. 584-592. Date of Electronic Publication: 2023 Sep 21.
DOI: 10.1038/s41386-023-01736-8
Abstrakt: Major depressive disorder (MDD) is a serious psychiatric disorder that in extreme cases can lead to suicide. Evidence suggests that alterations in the kynurenine pathway (KP) contribute to the pathology of MDD. Activation of the KP leads to the formation of neuroactive metabolites, including kynurenic acid (KYNA) and quinolinic acid (QUIN). To test for changes in the KP, postmortem anterior cingulate cortex (ACC) was obtained from the National Institute of Health NeuroBioBank. Gene expression of KP enzymes and relevant neuroinflammatory markers were investigated via RT-qPCR (Fluidigm) and KP metabolites were measured using liquid chromatography-mass spectrometry in tissue from individuals with MDD (n = 44) and matched nonpsychiatric controls (n = 36). We report increased IL6 and IL1B mRNA in MDD. Subgroup analysis found that female MDD subjects had significantly decreased KYNA and a trend decrease in the KYNA/QUIN ratio compared to female controls. In addition, MDD subjects that died by suicide had significantly decreased KYNA in comparison to controls and MDD subjects that did not die by suicide, while subjects that did not die by suicide had increased KYAT2 mRNA, which we hypothesise may protect against a decrease in KYNA. Overall, we found sex- and suicide-specific alterations in the KP in the ACC in MDD. This is the first molecular evidence in the brain of subgroup specific changes in the KP in MDD, which not only suggests that treatments aimed at upregulation of the KYNA arm in the brain may be favourable for female MDD sufferers but also might assist managing suicidal behaviour.
(© 2023. The Author(s).)
Databáze: MEDLINE
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