Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia.
Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia.
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DOI：
10.1038/s41380-019-0401-9
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发表时间：
2020-11
影响因子：
11
通讯作者：
Weickert TW
中科院分区：
文献类型：
--
作者：
Kindler J;Lim CK;Weickert CS;Boerrigter D;Galletly C;Liu D;Jacobs KR;Balzan R;Bruggemann J;O'Donnell M;Lenroot R;Guillemin GJ;Weickert TW
色氨酸（TRP）分解代谢的犬尿氨酸途径（KP）将免疫系统激活与神经递质信号传导联系起来。KP代谢产物kynuric acid （KYNA）在精神分裂症患者的大脑中增加。我们测试了：(1)脑KP酶mrna，(2)脑KP代谢物，(3)血浆KP代谢物在精神分裂症患者与对照组细胞因子升高的基础上的差异程度，以及血浆KP代谢物与周围细胞因子升高患者的认知和脑容量相关的程度。KP酶mrna和代谢物在来自71名精神分裂症患者和72名对照者的两个独立的死后脑样本中进行了分析。在96名精神分裂症患者和81名健康对照者的独立队列中测量血浆KP代谢物、认知和脑容量。各组根据升高与正常促炎细胞因子mRNA水平分层。在前额皮质（PFC）中，高细胞因子精神分裂症亚组犬尿氨酸(KYN)/TRP比率、KYNA水平以及色氨酸双加氧酶（TDO）和犬尿氨酸氨基转移酶（KATI/II） mRNA水平显著升高。KAT mRNA与患者胶质原纤维酸性蛋白mRNA显著相关。在血浆中，高细胞因子精神分裂症亚组显示KYN/TRP比值升高，这与注意力和背外侧前额叶皮质（DLPFC）体积呈负相关。这项研究为炎症在精神分裂症患者亚组中的作用提供了进一步的证据，并提出了炎症可能导致精神分裂症的分子机制。促炎细胞因子可引起外周TRP向KYN的转化，并通过增加脑星形胶质细胞中KAT mRNA和可能增加的酶合成活性，增加n -甲基-d-天冬氨酸受体拮抗剂KYNA，导致精神分裂症患者DLPFC体积减少和注意力障碍。
The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-d-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.
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影响因子：
11
作者：
Felger JC;Haroon E;Patel TA;Goldsmith DR;Wommack EC;Woolwine BJ;Le NA;Feinberg R;Tansey MG;Miller AH
通讯作者：
Miller AH
影响因子：
--
作者：
Gur, RE;Cowell, PE;Gur, RC
通讯作者：
Gur, RC
影响因子：
4.7
作者：
Guidetti, Paolo;Amori, Laura;Schwarcz, Robert
通讯作者：
Schwarcz, Robert
影响因子：
7.6
作者：
Chiappelli, Joshua;Rowland, Laura M.;Hong, L. Elliot
通讯作者：
Hong, L. Elliot
影响因子：
9.3
作者：
Boerrigter D;Weickert TW;Lenroot R;O'Donnell M;Galletly C;Liu D;Burgess M;Cadiz R;Jacomb I;Catts VS;Fillman SG;Weickert CS
通讯作者：
Weickert CS