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.

项目摘要 有融合的证据表明，kynurenine途径灾难可能与 精神分裂症的病理生理。特别是，临床，遗传和验尸研究表明 关键调节途径酶的破坏会导致中枢神经系统产生的Kynurenic Acid（Kyna）增加； ±-7烟碱和N-甲基-D-天冬氨酸（NMDA）谷氨酸受体的已知拮抗剂。 kyna 这些受体的拮抗作用被认为是认知发展的关键机制 精神分裂症中观察到的障碍。在我们以前的工作中，我们证明了Kyna增加 （遵循色氨酸（TRYP）挑战）在健康中的口头和视觉记忆测试中学习受损 控件。此外，我们发现kyna增加了整个大脑和额叶灰质物质 精神分裂症患者的脑血流（CBF）；重要的是，较低的静息CBF与较差有关 精神分裂症的认知功能。此外，我们确定了一个精神分裂症的亚组 血清Kyna水平升高，其特征是BPR总数较高，积极症状和思想 疾病因子得分；谁在持续关注的情况下对自己的表现充满了担忧 TRIP之后的任务，但不是安慰剂，管理。最后，我们最近报道了较高的循环kyna 与人类中脑谷氨酸的下脑谷氨酸相关，并提供了较高脑kyna的初步证据 与下白质分数各向异性有关。这些结果的收敛性提供了进一步的 支持Kyna增加的假设与认知障碍的病理生理有关 精神分裂症。拟议的研究旨在检查NAC是否阻止了 通过KAT II的脑功能，结构，化学和行为的选定度量增加Kyna 抑制。该研究将是一项双盲，安慰剂对照的，随机的交叉挑战研究， 精神分裂症患者用高剂量NAC（140 mg/kg）预处理最多15 G或安慰剂，然后接受6 gms的锥虫。我们将收集基线和治疗后临床，认知， 电生理，实验室和神经影像学措施。我们将检查NAC是否与 安慰剂阻止kynurenine向Kyna的外围转化；减弱tr型ASL CBF的影响 措施；并增加白质完整性的扩散加权成像（DWI）指数； ERP 半球间转移；和谷氨酸夫人措施。我们还将检查NAC是否对 上述神经影像措施与注意力，言语和视觉的认知度量的变化有关 内存和工作记忆。最后，我们将检查基线血清Kyna水平和/或PBMC水平是否 Kynurenine 3-酮氧酶（KMO）活性与NAC对拟议结果的影响有关 措施。 NAC逆转Kyna水平的不利影响的证明将重要 支持Kat II抑制剂的发展，以增强精神分裂症的认知。