GABA-A alpha5 cognitive enhancers: pharmacology and neuropsychology in macaques

GABA-A α5 认知增强剂：猕猴的药理学和神经心理学

• 批准号: 7486744
• 负责人: Nancy A. Ator
• 金额: $ 38.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486744
• 关键词: Adverse effects; Age; Agonist; Alzheimer' s Disease; Area; Attenuated; Basic Science; Behavioral; Benzodiazepine Receptor; Benzodiazepines; Binding Sites; Biological Assay; Brain; Cardiovascular system; Caring; Cholinergic Agents; Class; Clinical; Cognition; Cognitive; Complex; Development; Devices; Dimensions; Disease; Dose; Economics; Effectiveness; Evaluation; Family; Hippocampus (Brain); Impaired cognition; Impairment; Implant; In Vitro; Ions; Laboratories; Ligands; Macaca; Macaca mulatta; Measures; Mediating; Memory; Minor; Monkeys; Mus; Neuroanatomy; Neuropharmacology; Neuropsychological Tests; Neuropsychology; Nootropic Agents; Organ; Outcome; Palliative Care; Pathologist; Patients; Performance; Pharmacology; Population; Primates; Quality of life; Radio; Range; Research; Research Personnel; Rodent; Rodent Model; Sampling; Scopolamine; Site; Specificity; Structure; Techniques; Telemetry; Testing; Therapeutic; Toxic effect; Toxicity Tests; Training; Translational Research; Treatment Cost; United States; cholinergic; cognitive function; cohort; cooking; cost; direct application; experience; gamma-Aminobutyric Acid; improved; in vivo; innovation; interdisciplinary approach; mild neurocognitive impairment; neuropsychological; nonhuman primate; novel; programs; receptor; respiratory; response

DESCRIPTION (provided by applicant): Cognitive impairment is a debilitating outcome of Alzheimer's Disease and Minor Cognitive Impairment. Cognitive impairment reduces quality of life and increases treatment costs. Relatively modest increases in cognitive function produce relatively large increases in quality of life and large decreases in cost of care. Palliative treatments enhancing cognitive function would benefit many patients until treatments for their underlying disorders are developed. One promising pharmacological target for such cognitive enhancers is the benzodiazepine (BZ) binding site on the gamma-aminobutyric acid (GABA) type A (GABAA) receptor- complex. Subtype-selective ligands have been developed for the GABAA-a5 BZ receptor (GABAAa5- BZr), which is predominately expressed in the hippocampus, a site important for memory function. Studies in rodent and nonhuman primate memory assays indicate that GABAAa5-BZr inverse agonists improve cognition with few adverse effects. In the proposed studies, 8 rhesus monkeys will be trained to perform tests from the CANTAB nonhuman primate neuropsychological testing battery. 4 monkeys will be also be trained on the delayed-match-to- sample test and implanted with radio-telemetry devices to measure cardiovascular and respiratory responses for dose-ranging studies. The dose-ranging cohort will determine active doses of the compounds in primates and also screen for compounds producing adverse effects prior to full cognitive testing in the CANTAB-trained monkeys. Novel compounds will be tested for toxicity in mice prior to testing in the dose- ranging or CANTAB-trained monkeys. The effects of GABAAa5-BZr ligands on cognitive function in macaques will be determined by pretreatments of GABAAa5-BZr agonists, antagonists and inverse agonists. These studies will test the hypothesis that activity at the GABAAa5-BZr can bi-directionally modulate cognition with agonists impairing cognitive performance and inverse agonists enhancing performance. The regional specificity of the CANTAB neuropsychological test battery will also allow for testing of the hypothesis that GABAAa5-BZr cognitive modulation will occur in tests mediated by temporal brain structures (i.e. the hippocampus) as opposed to tests mediated by frontal cortical structures. In addition, the ability of GABAAa5-BZr inverse agonists to reverse scopolamine-induced cognitive impairment will determine the potential effectiveness of these compounds as treatments for the cognitive impairment produced by Alzheimer's disease. Understanding the effects of GABAAa5-BZr ligands has important implications to the neuro- pharmacology, neuropsychology and neuroanatomy of cognition and will further development of a novel class of therapeutics for cognitive dysfunction in Alzheimer's disease and Minor Cognitive Impairment.

描述（由申请人提供）：认知障碍是阿尔茨海默病和轻微认知障碍的一种使人衰弱的结果。认知障碍会降低生活质量并增加治疗费用。认知功能相对适度的提高会带来相对较大的生活质量提高和护理费用的大幅降低。在开发出针对其潜在疾病的治疗方法之前，增强认知功能的姑息治疗将使许多患者受益。这种认知增强剂的一个有前景的药理学靶点是γ-氨基丁酸（GABA）A 型（GABAA）受体复合物上的苯二氮卓（BZ）结合位点。已经为 GABAA-a5 BZ 受体 (GABAAa5-BZr) 开发了亚型选择性配体，该受体主要在海马体中表达，海马体是记忆功能的重要部位。啮齿类动物和非人类灵长类动物记忆测定研究表明，GABAAa5-BZr 反向激动剂可改善认知能力，且副作用很少。在拟议的研究中，将训练 8 只恒河猴进行 CANTAB 非人类灵长类神经心理学测试电池的测试。 4 只猴子还将接受延迟样本匹配测试的训练，并植入无线电遥测设备，以测量心血管和呼吸系统反应，以进行剂量范围研究。剂量范围队列将确定灵长类动物中化合物的活性剂量，并在对 CANTAB 训练的猴子进行全面认知测试之前筛选产生副作用的化合物。在对剂量范围或经过 CANTAB 训练的猴子进行测试之前，将先在小鼠中测试新型化合物的毒性。 GABAAa5-BZr 配体对猕猴认知功能的影响将通过 GABAAa5-BZr 激动剂、拮抗剂和反向激动剂的预处理来确定。这些研究将检验以下假设：GABAAa5-BZr 的活动可以双向调节认知，激动剂会损害认知表现，反激动剂会增强表现。 CANTAB 神经心理学测试组的区域特异性还将允许测试以下假设：GABAAa5-BZr 认知调节将发生在由颞脑结构（即海马体）介导的测试中，而不是由额叶皮层结构介导的测试中。此外，GABAAa5-BZr反向激动剂逆转东莨菪碱诱导的认知障碍的能力将决定这些化合物作为治疗阿尔茨海默病引起的认知障碍的潜在有效性。了解 GABAAa5-BZr 配体的作用对认知的神经药理学、神经心理学和神经解剖学具有重要意义，并将进一步开发一类治疗阿尔茨海默病和轻微认知障碍认知功能障碍的新型疗法。