Role of kynurenic acid in higher cognitive deficits: Mechanism and treatment strategies

犬尿酸在较高认知缺陷中的作用：机制和治疗策略

• 批准号: 10715487
• 负责人: MIN WANG
• 金额: $ 216.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715487
• 关键词: Acids; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Animal Model; Attention; Behavioral; Behavioral Assay; Brain; COVID-19; COVID-19 pandemic; Cells; Cholinergic Receptors; Cholinesterase Inhibitors; Clinical; Cognition Disorders; Cognitive deficits; Combined Modality Therapy; Coupled; Data; Disease; Dose; Elderly; Elderly woman; Enzymes; Family; Galantamine; Generations; Glycine; Impaired cognition; Impairment; Infection; Inflammation; Inflammatory; Iontophoresis; Kynurenic Acid; Kynurenine; Long COVID; Macaca mulatta; Memory impairment; Metabolism; Molecular; Monkeys; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Oral Administration; Pathology; Pathway interactions; Patients; Performance; Physiological; Physiology; Plasma; Prefrontal Cortex; Primates; Process; Production; Property; Reducing Agents; Regimen; Regulation; Research; Rodent; Role; SARS-CoV-2 infection; Sensory; Sepsis; Serine; Short-Term Memory; Signal Transduction; Site; Study models; Synapses; Testing; Therapeutic; Time; Translating; Tryptophan; aged; aging brain; alpha-bungarotoxin receptor; antagonist; cholinergic; clinically relevant; cognitive ability; cognitive performance; executive function; experimental study; inhibitor; insight; neurotransmission; oculomotor; optimal treatments; permissiveness; pharmacologic; positive allosteric modulator; receptor; response; side effect; tau Proteins; translation to humans; treatment strategy

The proposed research will examine whether increased kynurenine inflammatory signaling with advancing age impairs higher cortical function through blockade of NMDAR and α7-nAChR, producing cognitive deficits that can be reversed by agents that inhibit kynurenine metabolism. Inflammation induces the conversion of tryptophan to kynurenine, a process that increases with age, and becomes especially prominent in Alzheimer’s Disease (AD), and with infection (e.g. from COVID19). Importantly, kynurenine is further metabolized to kynurenic acid (KYNA), which blocks NMDAR and likely α7-nAChR. Our research has shown that the working memory-related firing of “Delay cells” in primate dorsolateral prefrontal cortex (dlPFC) is heavily dependent on NMDAR neurotransmission with permissive α7-nAChR actions. As KYNA blocks both of these receptors, the increased production of KYNA in the aging brain may be particularly detrimental to dlPFC neuronal firing, and may contribute to the reduced dlPFC neuronal firing and working memory deficits observed in aged monkeys. The proposed research will perform the first examination of KYNA actions on primate dlPFC neuronal firing during working memory in young vs. aged rhesus monkeys, and will test for its interactions with NMDAR and α7-nAChR. We will also examine strategies to restore neuronal firing and working memory performance in aged monkeys by reducing KYNA production, coupled with enhanced cholinergic actions to optimize dlPFC neuronal physiology. These data may provide strategies to protect higher cortical circuits in cognitive disorders with high levels of KYNA production such as AD. Aim 1 will examine how local iontophoresis of exogenously applied KYNA (Aim 1A), or agents that alter the endogenous generation of KYNA (Aim 1B), influences Delay cell firing in young and aged monkeys. Preliminary data indicate that KYNA greatly reduces working memory- related neuronal firing, and that inhibition of KYNA synthesis can boost delay-related firing in aged monkey neurons. Aim 2 will test for KYNA actions at the glycine site on the NMDAR (Aim 2A), and at α7-nAChR (Aim 2B) in dlPFC, testing the hypothesis that KYNA blockade of these receptors markedly reduces Delay cell firing. Preliminary data are consistent with KYNA having both NMDAR and α7-nAChR blocking properties. Aim 3 will examine strategies to optimally restore dlPFC Delay cell firing (Aim 3A) and working memory performance (Aim 3B) in aged monkeys by combining agents that inhibit KYNA production with galantamine, a cholinesterase inhibitor and α7-nAChR positive allosteric modulator that is already approved for the treatment of AD. Given that dlPFC Delay cells require both NMDAR and α7-nAChR stimulation to sustain firing, we hypothesize that this combination may optimize dlPFC physiology and working memory performance in aged monkeys. The use of oral administration of compounds in Aim 3B may identify dosing regimens that can facilitate translation to human use, boosting higher cognitive abilities in patients with AD or other inflammatory disorders, e.g. “long-COVID”, associated with dlPFC cognitive deficits and high levels of kynurenine.

这项拟议的研究将检验犬尿氨酸炎症信号是否随着年龄的增长而增加 通过阻断nmdar和α7-nAChR，损害高级皮质功能，产生认知缺陷， 可被抑制犬尿氨酸代谢的药物逆转。炎症诱导转化为 色氨酸转化为犬尿氨酸的过程随着年龄的增长而增加，在阿尔茨海默氏症中尤为突出 疾病(AD)和感染(例如来自COVID19)。重要的是，犬尿氨酸被进一步代谢成 犬尿酸(KYNA)，它阻断NMDAR和可能的α7-nAChR。我们的研究表明， 灵长类背外侧前额叶皮质(DlPFC)“延迟细胞”的记忆相关放电在很大程度上依赖于 允许α7-nAChR作用的NMDAR神经传递。由于KYNA阻断了这两种受体， 在老化的大脑中，KYNA的产生增加可能对dlPFC神经元的放电特别有害，并且 可能有助于减少老年猴子的dlPFC神经元放电和工作记忆缺陷。 这项拟议的研究将首次检验KYNA对灵长类dlPFC神经元放电的作用。 在年轻恒河猴和老年恒河猴的工作记忆过程中，并将测试其与NMDAR和 α7-nAChR。我们还将研究恢复神经元放电和工作记忆性能的策略 通过减少KYNA的产生和增强的胆碱能作用来优化dlPFC来老化猴子 神经生理学。这些数据可能为在认知障碍中保护高级皮质回路提供策略。 具有高水平的KYNA生产，如AD。目标1将研究局部离子导入如何外源性 应用KYNA(Aim 1A)或改变KYNA内源性生成的药物(Aim 1B)影响延迟 幼猴和老年猴的细胞放电。初步数据显示，KYNA大大减少了工作记忆- 相关神经元放电，抑制KYNA合成可促进老年猴延迟相关放电 神经元。AIM 2将在NMDAR上的甘氨酸位置(AIM 2A)和α7-nAChR(AIM)上测试KYNA的作用 2B)在dlPFC中，测试KYNA阻断这些受体显著减少延迟细胞激活的假设。 初步数据与KYNA同时具有NMDAR和α7-nAChR阻断性是一致的。目标3将 研究以最佳方式恢复dlPFC延迟单元触发(目标3A)和工作内存性能的策略 (AIM 3B)在老年猴子中，通过将抑制KYNA产生的药物与加兰他明联合使用， 胆碱酯酶抑制剂和α7-nAChR阳性变构调节剂已被批准用于治疗 公元一代的。鉴于dlPFC延迟细胞需要nmdar和α7-nAChR刺激才能维持放电，我们 假设这种组合可能会优化老年人的dlPFC生理和工作记忆表现 猴子。在AIM 3B中使用口服给药可以识别可以 促进翻译为人类使用，提高AD或其他炎症性疾病患者的认知能力 与dlPFC认知缺陷和高水平犬尿氨酸相关的疾病，如“长冠状病毒病”。