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.

拟议的研究将检查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 可以通过抑制犬尿氨酸代谢的药物来逆转炎症诱导的转化。 色氨酸到犬尿氨酸，这一过程随着年龄的增长而增加，在阿尔茨海默病中尤为突出 疾病（AD）和感染（例如新冠病毒），犬尿氨酸进一步代谢为。 犬尿酸 (KYNA)，它可以阻断 NMDAR 和可能的 α7-nAChR。 灵长类动物背外侧前额叶皮层（dlPFC）中与记忆相关的“延迟细胞”放电很大程度上依赖于 NMDAR 神经传递具有允许的 α7-nAChR 作用，因为 KYNA 阻断这两种受体， 衰老大脑中 KYNA 的产生增加可能对 dlPFC 神经元放电特别有害，并且 可能导致老年猴子中观察到的 dlPFC 神经放电和工作记忆缺陷减少。 拟议的研究将首次检查 KYNA 对灵长类动物 dlPFC 神经放电的作用 在年轻恒河猴和老年恒河猴的工作记忆期间，将测试其与 NMDAR 和 NMDAR 的相互作用 我们还将研究恢复神经放电和工作记忆性能的策略。 通过减少 KYNA 的产生，结合增强胆碱能作用来优化 dlPFC，对老年猴子进行治疗 神经元生理学。这些数据可能提供保护认知障碍中的高级皮质回路的策略。 目标 1 将检查外源性局部离子电渗疗法如何产生高水平的 KYNA。 应用 KYNA（目标 1A）或改变 KYNA 内源生成的试剂（目标 1B）会影响延迟 初步数据表明，KYNA 大大降低了工作记忆。 相关的神经放电，并且抑制 KYNA 合成可以促进老年猴子的延迟相关放电 目标 2 将测试 KYNA 在 NMDAR 甘氨酸位点（目标 2A）和 α7-nAChR（目标）的作用。 2B) 在 dlPFC 中，检验 KYNA 阻断这些受体显着减少延迟细胞放电的假设。 初步数据与 KYNA 具有 NMDAR 和 α7-nAChR Aim 3 阻断特性一致。 检查最佳恢复 dlPFC 延迟细胞放电（目标 3A）和工作记忆性能的策略 （目标 3B）通过将抑制 KYNA 产生的药物与加兰他敏（一种 胆碱酯酶抑制剂和 α7-nAChR 正变构调节剂已被批准用于治疗 鉴于 dlPFC 延迟细胞需要 NMDAR 和 α7-nAChR 刺激来维持放电，我们 老年人 dlPFC 生理学和工作记忆性能 在 Aim 3B 中使用口服化合物可以确定可以的给药方案。 促进转化为人类使用，提高 AD 或其他炎症患者的认知能力 与 dlPFC 认知缺陷和高水平犬尿氨酸相关的疾病，例如“长期新冠肺炎”。