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: 10016398
• 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/10016398
• 关键词: Acetylcysteine; Address; Adverse effects; Aftercare; Anisotropy; Attention; Attenuated; Autopsy; Behavior; Brain; Cerebrovascular Circulation; Cerebrum; 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; Placebos; Prefrontal Cortex; Production; Proteins; Randomized; Rattus; Recombinants; Regulatory Pathway; Reporting; Rest; Schizophrenia; Serum; Short-Term Memory; Structural Chemistry; Subgroup; Symptoms; Testing; Tryptophan; Visual attention; Work; brain tissue; cognitive development; cognitive function; design; enzyme activity; enzyme pathway; extracellular; gray matter; improved; indexing; inhibitor/antagonist; 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.

项目总结