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逆转。炎症诱导转化为 色氨酸转化为犬尿氨酸，这一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COVID 19）。重要的是，犬尿氨酸被进一步代谢为 犬尿烯酸（KYNA），其阻断NMDAR和可能的α7-nAChR。我们的研究表明， 灵长类背外侧前额叶皮层（dlPFC）中与记忆相关的“延迟细胞”放电在很大程度上依赖于 具有允许的α7-nAChR作用的NMDAR神经传递。由于KYNA阻断了这两种受体， 衰老大脑中KYNA产生的增加可能对dlPFC神经元放电特别有害， 可能有助于减少老年猴中观察到的dlPFC神经元放电和工作记忆缺陷。 这项拟议的研究将首次检查KYNA对灵长类dlPFC神经元放电的作用 在年轻与老年恒河猴的工作记忆中，并将测试其与NMDAR的相互作用， α7-nAChR。我们还将研究恢复神经元放电和工作记忆表现的策略， 通过减少KYNA的产生，加上增强的胆碱能作用来优化dlPFC， 神经元生理学。这些数据可能会提供策略，以保护认知障碍的高级皮层回路 具有高水平的KYNA生产，例如AD。目的1将研究如何局部离子导入外源性 应用KYNA（目的1A）或改变KYNA内源性产生的药物（目的1B）， 年轻和年老猴子的细胞放电。初步数据表明，KYNA大大降低了工作记忆- 相关的神经元放电，并且抑制KYNA合成可以增强老年猴的延迟相关放电 神经元目标2将检测KYNA在NMDAR（目标2A）甘氨酸位点和α7-nAChR（目标2A）上的作用 2B）在dlPFC中，测试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阻断特性一致。目标3将 检查策略，以最佳地恢复dlPFC延迟细胞发射（目标3A）和工作记忆的性能 (Aim 3B）通过将抑制KYNA产生的药剂与加兰他敏组合， 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 的AD。考虑到dlPFC延迟细胞需要NMDAR和α7-nAChR刺激来维持放电，我们 假设这种组合可以优化老年人dlPFC生理学和工作记忆表现， 猴子目的3B中的化合物的口服给药的使用可以确定可以 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COVID”。