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Kynurenine炎症信号是否随着年龄的增长而增加 通过封锁NMDAR和α7-NACHR损害较高的皮质功能，从而产生认知缺陷 抑制kynurenine代谢的药物可以逆转。炎症诱导 色氨酸到kynurenine，这一过程随着年龄的增长而增加，并且在阿尔茨海默氏症中尤为突出 疾病（AD）和感染（例如，Covid19）。重要的是，kynurenine进一步代谢 Kynurenic Acid（Kyna），它阻断了NMDAR和可能的α7-NACHR。我们的研究表明，工作 私有双层叶状额叶皮层（DLPFC）中与内存相关的“延迟细胞”的发射很大程度上取决于 NMDAR神经传递采用允许的α7-NACHR作用。当Kyna阻止这两个受体时， 衰老大脑中Kyna的产生可能特别有害于DLPFC神经元发射，并且 可能有助于降低的DLPFC神经元放电，并且工作记忆定义了在老年猴子中观察到的。 拟议的研究将对Kyna对灵长类动物DLPFC神经元射击进行首次检查 在年轻人与老年恒河猴的工作记忆期间，将测试其与NMDAR和 α7-nachr。我们还将研究恢复神经元射击和工作记忆性能的策略 通过减少Kyna的产生，再加上增强的胆碱能作用来优化DLPFC，通过减少Kyna的产生来优化老化的猴子 神经元生理学。这些数据可能会提供保护认知障碍中较高皮质电路的策略 具有高水平的Kyna产量，例如AD。 AIM 1将检查外源的局部离子噬菌体 应用的kyna（AIM 1A）或改变内源性Kyna（AIM 1B）的药物会影响延迟 年轻和老年猴子的细胞发射。初步数据表明Kyna大大降低了工作记忆 - 相关的神经元发射和抑制Kyna合成可以增强老年猴子的延迟触发 神经元。 AIM 2将在NMDAR（AIM 2A）和α7-NACHR上测试Kyna作用 2b）在DLPFC中，检验了这些受体阻断的假设显着减少了延迟细胞的发射。 初步数据与具有NMDAR和α7-NACHR阻塞特性的KynA一致。目标3意志 检查策略以最佳恢复DLPFC延迟电池发射（AIM 3A）和工作记忆性能 （AIM 3B）通过将抑制Kyna产生的甘氨酸的剂相结合，在老化的猴子中 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 广告。鉴于DLPFC延迟细胞需要NMDAR和α7-NACHR刺激才能维持点火，因此我们 假设这种组合可以优化老年人的DLPFC生理学和工作记忆表现 猴子。在AIM 3B中使用口服化合物的使用可能会确定可以识别可以 促进转化为人类使用，增强AD或其他炎症患者的认知能力较高 疾病，例如“长卵巢”，与DLPFC认知缺陷和高水平的kynurenine有关。