The Effects of Kynurenine Aminotransferase Inhibition in People with Schizophrenia

犬尿氨酸转氨酶抑制对精神分裂症患者的影响

• 批准号: 10661742
• 负责人: ROBERT W BUCHANAN
• 金额: $ 88.86万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661742
• 关键词: Acetylcysteine; Adverse effects; Aftercare; Anisotropy; Attention; Attenuated; Autopsy; Behavior; Brain; Cerebrovascular Circulation; Cerebrum; Chemistry; Clinical; Clinical Treatment; Cognition; Cognitive; Development; Diffusion Magnetic Resonance Imaging; Disease; Dose; Double-Blind Method; Electrophysiology (science); Enzyme Inhibition; Enzymes; Exhibits; Family suidae; Functional disorder; Genetic; Glutamate Receptor; Glutamates; Glutathione; Human; Impaired cognition; Impairment; Kynurenic Acid; Kynurenine; Kynurenine 3-monooxygenase; Kynurenine-oxoglutarate aminotransferase; Laboratories; Learning; Liver; Measures; Microdialysis; Mus; N-Methylaspartate; Outcome Measure; Oxidative Stress; Pathway interactions; Performance; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Placebo Control; Placebos; Prefrontal Cortex; Production; Proteins; Randomized; Rattus; Recombinants; Regulatory Pathway; Reporting; Rest; Schizophrenia; Serum; Short-Term Memory; Structure; Subgroup; Symptoms; Testing; Tryptophan; Visual attention; Work; antagonist; brain tissue; cognitive function; design; enzyme activity; enzyme pathway; extracellular; frontal lobe; gray matter; improved; indexing; inhibitor; interest; interhemispheric transfer; kynurenine aminotransferase II; meter; neuroimaging; receptor; sustained attention; verbal; visual memory; white matter

PROJECT SUMMARY There is converging evidence to suggest that kynurenine pathway disturbances may be related to the pathophysiology of schizophrenia. In particular, clinical, genetic, and post-mortem studies suggest that the disruption of key regulatory pathway enzymes results in increased CNS production of kynurenic acid (KYNA); a known antagonist of ±-7 nicotinic and N-Methyl-D-aspartate (NMDA) glutamate receptors. The KYNA antagonism of these receptors is hypothesized to be a critical mechanism in the development of the cognitive impairments observed in schizophrenia. In our previous work, we demonstrated that increased KYNA (following tryptophan (TRYP) challenge) impaired learning on verbal and visual memory tests in healthy controls. In addition, we found that increased KYNA decreased whole brain and frontal cortical gray matter cerebral blood flow (CBF) in people with schizophrenia; importantly, lower resting CBF is related to poorer cognitive function in schizophrenia. Furthermore, we identified a subgroup of people with schizophrenia with elevated serum KYNA levels, who were characterized by higher BPRS total, positive symptom, and thought disorder factor scores; and who exhibited a significant worsening of their performance on a sustained attention task following TRYP, but not placebo, administration. Finally, we recently reported that higher circulating KYNA correlates with lower brain glutamate in humans and present preliminary evidence that higher brain KYNA is associated with lower white matter fractional anisotropy. The convergence of these results provides further support for the hypothesis that increased KYNA is related to the pathophysiology of cognitive impairments in schizophrenia. The proposed study is designed to examine whether NAC blocks the adverse effects of increased KYNA on selected measures of brain function, structure, chemistry, and behavior through KAT II inhibition. The study will be a double-blind, placebo-controlled, randomized cross-over challenge study, in which people with schizophrenia are pretreated with either high-dose NAC, 140 mg/kg up to a maximum of 15 g, or placebo, then receive TRYP, 6 gms. We will collect baseline and post-treatment clinical, cognitive, electrophysiological, laboratory, and neuroimaging measures. We will examine whether NAC compared to placebo blocks the peripheral conversion of kynurenine to KYNA; attenuates the effects of TRYP on ASL CBF measures; and increases diffusion weighted imaging (DWI) indices of white matter integrity; ERP interhemispheric transfer; and MRS glutamate measures. We will also examine whether the NAC effects on the above neuroimaging measures are related to changes in cognitive measures of attention, verbal and visual memory, and working memory. Finally, we will examine if baseline serum KYNA levels and/or PBMC kynurenine 3-monooxygenase (KMO) activity are related to the effects of NAC on the proposed outcome measures. The demonstration that NAC reverses the adverse impact of increased KYNA levels will importantly support the development of KAT II inhibitors for the enhancement of cognition in schizophrenia.

项目总结 越来越多的证据表明，犬尿氨酸途径紊乱可能与 精神分裂症的病理生理学。特别是，临床、遗传和尸检研究表明 破坏关键调控途径酶导致中枢神经系统犬尿酸(KYNA)产量增加；a 已知的烟碱和N-甲基-D-天冬氨酸(NMDA)谷氨酸受体的拮抗剂。朝中社 这些受体的拮抗被认为是认知发展的关键机制。 在精神分裂症中观察到的损害。在我们之前的工作中，我们证明了增加KYNA (遵循色氨酸(TRYP)挑战)健康人在言语和视觉记忆测试中学习受损 控制。此外，我们发现KYNA的增加减少了整个大脑和额叶皮质灰质 精神分裂症患者的脑血流量(CBF)；重要的是，静息脑血流量低与较差有关 精神分裂症患者的认知功能。此外，我们确定了精神分裂症患者的一个亚组 血清KYNA水平升高，其特征是BPR总分、阳性症状和思维水平较高 障碍因子得分；以及在持续注意力上表现出显著恶化的人 任务遵循TRYP，但不是安慰剂，给药。最后，我们最近报道说，更高的循环KYNA 与人类较低的大脑谷氨酸相关，并提供了初步证据表明，较高的大脑KYNA是 与较低的白质分数各向异性有关。这些结果的收敛进一步提供了 支持KYNA增加与认知障碍的病理生理学有关的假说 精神分裂症。这项拟议的研究旨在检查NAC是否阻止了 通过Kat II在选定的大脑功能、结构、化学和行为指标上提高KYNA 抑制力。这项研究将是一项双盲、安慰剂对照、随机交叉挑战研究，在 哪些精神分裂症患者接受大剂量NAC，140 mg/kg至最高15 mg/kg的预处理 G，或安慰剂，然后接受TRYP，6克。我们将收集基线和治疗后的临床、认知、 电生理、实验室和神经成像测量。我们将研究新来华儿童与 安慰剂阻断犬尿氨酸向KYNA的外周转化；减弱TRYP对ASL CBF的影响 测量；并增加脑白质完整性的扩散加权成像(DWI)指数； 大脑半球间转移；谷氨酸夫人测量。我们亦会研究新来港定居人士会否对 上述神经成像测量与注意力、语言和视觉的认知测量的变化有关 记忆和工作记忆。最后，我们将检查基线血清KYNA水平和/或PBMC 犬尿氨酸3-单加氧酶(KMO)活性与NAC对预后的影响有关 措施。证明NAC扭转了KYNA水平上升的不利影响将是重要的 支持开发Kat II抑制剂以增强精神分裂症患者的认知能力。