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

基本信息

批准号：
7916676
负责人：
Nancy A. Ator
金额：
$ 39.86万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/7916676
关键词：
Adverse effects Age Agonist Alzheimer&apos s Disease Area Attenuated Basic Science Behavioral Benzodiazepine Receptor Benzodiazepines Binding Sites Biological Assay Brain Cardiovascular system Caring Clinical Cognition Cognitive Complex Development Devices Dimensions Disease Dose 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 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 enhancement cognitive function cohort cooking cost direct application economic impact experience gamma-Aminobutyric Acid improved in vivo innovation interdisciplinary approach mild neurocognitive impairment neuropsychological nonhuman primate novel programs receptor respiratory response

项目摘要

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氏病和轻微认知障碍的令人衰弱的结果。认知障碍会降低生活质量并增加治疗成本。认知功能的相对较小的增加产生了相对较大的生活质量增加，并且护理成本的大幅下降。增强认知功能的姑息治疗将使许多患者受益，直到开发了其潜在疾病的治疗。这种认知增强剂的一个有希望的药理学靶标是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）开发了亚型选择配体，该配体主要在海马中表达，这是一个对记忆函数重要的位点。对啮齿动物和非人类灵长类动物记忆测定法的研究表明，GabaAA5-BZR反向激动剂会改善认知，几乎没有不利影响。在拟议的研究中，将对8只恒河猴进行训练，从而从Cantab非人类灵长类动物神经心理学测试电池进行测试。 4猴子还将接受延迟匹配样品测试的训练，并使用无线电训练装置植入，以测量剂量范围研究的心血管和呼吸反应。剂量范围的队列将确定灵长类动物中化合物的活性剂量，并筛选出在cantab训练的猴子进行全认知测试之前产生不良反应的化合物。新型化合物将在剂量或cantab训练的猴子进行测试之前对小鼠的毒性进行测试。 GABAAA5-BZR配体对猕猴认知功能的影响将由GABAAAA5-BZR激动剂，拮抗剂和逆激动剂的预处理确定。这些研究将检验以下假设：GABAAA5-BZR的活性可以双向调节认知，而动力学家会损害认知表现和反向激动剂增强性能。 CANTAB神经心理测试电池的区域特异性还将允许测试以下假设：与额叶皮质结构介导的测试相比，在颞脑结构（即海马）介导的测试中将发生GABAAA5-BZR认知调节。此外，GABAAA5-BZR反向激动剂逆转占地造成的认知障碍的能力将确定这些化合物作为阿尔茨海默氏病的认知障碍的治疗方法的潜在有效性。了解GABAAA5-BZR配体的影响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，并将进一步发展出对阿尔茨海默氏病认知功能障碍的新型治疗学，以及次要认知障碍。