Notarangelo Francesca M, Pocivavsek Ana
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
Neuropharmacology. 2017 Jan;112(Pt B):275-285. doi: 10.1016/j.neuropharm.2016.03.001. Epub 2016 Mar 2.
The kynurenine pathway (KP) of tryptophan degradation contains several neuroactive metabolites that may influence brain function in health and disease. Mounting focus has been dedicated to investigating the role of these metabolites during neurodevelopment and elucidating their involvement in the pathophysiology of psychiatric disorders with a developmental component, such as schizophrenia. In this review, we describe the changes in KP metabolism in the brain from gestation until adulthood and illustrate how environmental and genetic factors affect the KP during development. With a particular focus on kynurenic acid, the antagonist of α7 nicotinic acetylcholine (α7nACh) and N-methyl-d-aspartate (NMDA) receptors, both implicated in modulating brain development, we review animal models designed to ascertain the role of perinatal KP elevation on long-lasting biochemical, neuropathological, and behavioral deficits later in life. We present new data demonstrating that combining perinatal choline-supplementation, to potentially increase activation of α7nACh receptors during development, with embryonic kynurenine manipulation is effective in attenuating cognitive impairments in adult rat offspring. With these findings in mind, we conclude the review by discussing the advancement of therapeutic interventions that would target not only symptoms, but potentially the root cause of central nervous system diseases that manifest from a perinatal KP insult. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.
色氨酸降解的犬尿氨酸途径（KP）包含几种具有神经活性的代谢产物，它们可能在健康和疾病状态下影响脑功能。越来越多的研究致力于探究这些代谢产物在神经发育过程中的作用，并阐明它们在具有发育成分的精神疾病（如精神分裂症）病理生理学中的作用。在这篇综述中，我们描述了从妊娠期到成年期大脑中KP代谢的变化，并阐述了环境和遗传因素在发育过程中如何影响KP。特别关注犬尿喹啉酸，它是α7烟碱型乙酰胆碱（α7nACh）和N-甲基-D-天冬氨酸（NMDA）受体的拮抗剂，这两种受体都与调节大脑发育有关，我们综述了旨在确定围产期KP升高对生命后期长期生化、神经病理学和行为缺陷作用的动物模型。我们展示了新的数据，表明在胚胎期操纵犬尿氨酸的同时，围产期补充胆碱以潜在增加发育过程中α7nACh受体的激活，可有效减轻成年大鼠后代的认知障碍。基于这些发现，我们在综述结尾讨论了治疗干预措施的进展，这些措施不仅针对症状，还可能针对由围产期KP损伤引起的中枢神经系统疾病的根本原因。本文是名为“健康与疾病中的犬尿氨酸途径”特刊的一部分。
