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: 10425364
• 负责人: ROBERT W BUCHANAN
• 金额: $ 60.33万
• 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/10425364
• 关键词: Acetylcysteine; Address; Adverse effects; Aftercare; Anisotropy; Attention; Attenuated; Autopsy; Behavior; Brain; Cerebrovascular Circulation; Cerebrum; Chemistry; Clinical Treatment; Cognition; Cognitive; Development; Diffusion Magnetic Resonance Imaging; Disease; Dose; Double-Blind Method; Electrophysiology (science); Enzymes; Exhibits; Family suidae; Functional disorder; Glutamate Receptor; Glutamates; Glutathione; Human; Impaired cognition; Impairment; Kynurenic Acid; Kynurenine; Kynurenine 3-monooxygenase; Kynurenine-oxoglutarate aminotransferase; Laboratories; Learning; Liver; Measures; Medical Genetics; 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 development; cognitive function; design; enzyme activity; enzyme pathway; extracellular; gray matter; improved; indexing; inhibitor; interest; interhemispheric transfer; kynurenine aminotransferase II; neuroimaging; receptor; sustained attention; 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.

项目概要 有一致的证据表明犬尿氨酸通路紊乱可能与 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 关键调节途径酶的破坏导致中枢神经系统犬尿酸 (KYNA) 的产生增加；一个 已知的 ±-7 烟碱和 N-甲基-D-天冬氨酸 (NMDA) 谷氨酸受体拮抗剂。凯纳 这些受体的拮抗作用被认为是认知能力发展的关键机制。 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 （色氨酸（TRYP）挑战后）健康人言语和视觉记忆测试中的学习障碍 控制。此外，我们发现 KYNA 增加会减少全脑和额叶皮质灰质 精神分裂症患者的脑血流量（CBF）；重要的是，较低的静息 CBF 与较差的 精神分裂症的认知功能。此外，我们还确定了一个精神分裂症患者亚群 血清 KYNA 水平升高，其特征是 BPRS 总数较高、症状呈阳性并且认为 紊乱因素评分；以及谁在持续关注下表现出明显恶化 TRYP（而非安慰剂）给药后的任务。最后，我们最近报道了更高的 KYNA 流通量 与人类较低的大脑谷氨酸相关，并提供初步证据表明较高的大脑 KYNA 与 与较低的白质各向异性分数相关。这些结果的融合进一步提供了 支持以下假设：KYNA 增加与认知障碍的病理生理学有关 精神分裂症。拟议的研究旨在检验 NAC 是否可以阻止以下不良反应： 通过 KAT II 增加 KYNA 对大脑功能、结构、化学和行为的选定测量的影响 抑制。该研究将是一项双盲、安慰剂对照、随机交叉挑战研究， 精神分裂症患者接受高剂量 NAC 预处理，140 毫克/公斤，最多 15 g，或安慰剂，然后接受 TRYP，6 gms。我们将收集基线和治疗后的临床、认知、 电生理学、实验室和神经影像学测量。我们将检查 NAC 是否与 安慰剂阻断犬尿氨酸到 KYNA 的外周转化；减弱 TRYP 对 ASL CBF 的影响 措施；并增加白质完整性的弥散加权成像（DWI）指数；企业资源计划 半球间转移；和 MRS 谷氨酸测量。我们还将检查 NAC 是否会影响 上述神经影像学测量与注意力、语言和视觉认知测量的变化有关 记忆力和工作记忆力。最后，我们将检查基线血清 KYNA 水平和/或 PBMC 是否 犬尿氨酸 3-单加氧酶 (KMO) 活性与 NAC 对拟议结果的影响有关 措施。 NAC 逆转 KYNA 水平增加的不利影响的证明将具有重要意义 支持开发 KAT II 抑制剂以增强精神分裂症的认知能力。