An in Vivo Neurogenesis Assay to Discover Antidepressants and Cognitive Enhancers

体内神经发生检测发现抗抑郁药和认知增强剂

• 批准号: 7335614
• 负责人: Mahalakshmi Shankaran
• 金额: $ 25万
• 依托单位: KINEMED, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7335614
• 关键词: Acute; Alzheimer' s Disease; Antidepressive Agents; Antipsychotic Agents; Behavioral; Behavioral Model; Biological Assay; Biological Markers; Blinded; Bromodeoxyuridine; Cell Differentiation process; Cell Proliferation; Chronic; Class; Classification; Clinical Research; Clinical Trials; Cognition; Cognition Disorders; Cognitive; Count; DNA; Deoxyribose; Deuterium; Deuterium Oxide; Development; Disease; Dose; Effectiveness; Evaluation; Goals; Hippocampus (Brain); Label; Lead; Licensing; Mass Spectrum Analysis; Measurement; Measures; Memory; Mental Depression; Methods; Metric; Modeling; Mood Disorders; Moods; Mus; Neurons; Nootropic Agents; Numbers; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Positioning Attribute; Process; Production; Proliferating; Radioisotopes; Rattus; Reaction Time; Safety; Schizophrenia; Screening procedure; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Standards of Weights and Measures; Stem cells; Swimming; Techniques; Testing; Therapeutic Agents; Thinking; Time; Toxic effect; Treatment Protocols; atypical antipsychotic; base; brain cell; concept; day; drug discovery; drug testing; early onset; high throughput screening; improved; in vivo; long term memory; neurogenesis; novel; novel therapeutics; object recognition; pre-clinical; response; stable isotope

DESCRIPTION (provided by applicant): Hippocampal neurogenesis represents a promising target for discovery of novel therapeutic agents for disorders of mood and cognition. All known antidepressants stimulate hippocampal neurogenesis and impaired neurogenesis may be etiologic in depression and schizophrenia. Systematic drug discovery and development (DDD) efforts have been hampered, however, by the limited throughput, precision and sensitivity of existing techniques for measuring neurogenesis in vivo (i.e., BrdU labeling and counting). To overcome these limitations, we developed a sensitive, high-throughput assay for measuring hippocampal progenitor cell proliferation and neurogenesis in vivo. Incorporation of the non-radioactive isotope, deuterium (2H), into deoxyribose moiety of DNA in proliferating progenitor cells is measured by mass spectrometry, after labeling mice with heavy water (2H2O) for 7-12 days. This assay reproducibly detects neurogenic actions of current antidepressants and identified pipeline anti-depressant agents and dose, among unknown compounds in blinded studies. Moreover, a screening initiative of 15 approved drugs resulted in discovery of two novel and patentable neurogenic agents (confirmed as class effects), representing proof-of-concept for the present proposal. The goal of this Phase I SBIR project is to discover novel neurogenic agents. Aim 1 is to apply this assay for screening of approximately 80 in-licensed compounds for neurogenic activity, focusing on greater activity and earlier onset of action. These agents are in-licensed by KineMed from pharmaceutical partner companies and have all completed preclinical or Phase I-II clinical studies, but were halted for reasons other than toxicity. Neurogenic agents identified by this approach will be evaluated intensively for potency (dose-response) and time to onset of action and will also be tested in standard behavioral models of antidepressant activity and cognition. The most promising agents will be used for lead optimization or directly carried forward into Phase IIa clinical trials with partners, as antidepressants and/or cognitive enhancers. In Aim 2, we will focus on neurogenic and behavioral effects of antipsychotic agents, to test the hypothesis that 'atypical' antipsychotics have effects on mood and cognition that involve enhancement of neurogenesis. The goal is to enable use of neurogenesis as a metric for preclinical evaluation of antipsychotics. In summary, these studies will use hippocampal neurogenesis for systematic pathway-based DDD in psychiatric and cognitive disorders. Disorders of mood and thought processes including depression, schizophrenia, and Alzheimer's disease, are common and debilitating. A remarkable and hopeful biologic finding is that an impaired capacity to produce new brain cells, termed neurogenesis, may contribute to these disorders and can be improved by drug treatment. We will use a powerful new method for measuring the production of new brain cells as a way to discover new drugs, and we will then test the effectiveness of these drugs on depression and memory.

描述（由申请人提供）：海马神经发生代表了发现新型治疗剂的有希望的目标，用于情绪和认知障碍。所有已知的抗抑郁药都刺激海马神经发生和神经发生受损可能是抑郁和精神分裂症的病因。但是，系统的药物发现与发育（DDD）的工作受到了有限的吞吐量，精度和敏感性，用于测量体内神经发生的技术（即BRDU标记和计数）。为了克服这些局限性，我们开发了一种灵敏的高通量测定法，用于测量体内海马祖细胞增殖和神经发生。在用重水（2H2O）将小鼠标记为7-12天之后，通过质谱法测量非放射性同位素氘（2H）在增殖祖细胞中DNA的脱氧核糖核酸部分。该测定可重复检测当前抗抑郁药的神经源性作用，并鉴定出盲目研究中未知化合物中的管道抗抑郁药和剂量。此外，对15种批准药物的筛查计划导致发现了两种新型且可申请的神经源性剂（被确认为班级效应），代表了本提案的概念证明。该阶段I SBIR项目的目标是发现新颖的神经源性剂。 AIM 1是将此测定法应用于筛选大约80种许可化合物以进行神经源性活性，重点是更大的活性和早期作用发作。这些药物是由制药合作伙伴公司的Kinemed授予的，并且都完成了临床前或I-II期临床研究，但由于毒性以外的原因而被停止。通过这种方法鉴定的神经源性剂将对效力（剂量反应）和发作时间进行深入评估，并将在抗抑郁活性和认知的标准行为模型中进行测试。最有前途的药物将用于铅优化，或直接与伴侣，抗抑郁药和/或认知增强子一起进入IIA期临床试验。在AIM 2中，我们将重点关注抗精神病药的神经源性和行为作用，以检验以下假设：“非典型”抗精神病药对涉及增强神经发生的情绪和认知具有影响。目的是使神经发生用作抗精神病药的临床前评估的度量。总而言之，这些研究将使用海马神经发生，用于基于精神病和认知疾病的基于系统途径的DDD。情绪和思维过程的疾病包括抑郁症，精神分裂症和阿尔茨海默氏病，是常见的，使人衰弱。一个了不起的生物学发现是，产生新的脑细胞的能力受损，称为神经发生，可能会导致这些疾病，并且可以通过药物治疗来改善。我们将使用一种强大的新方法来测量新的脑细胞的产生，以发现新药，然后我们将测试这些药物对抑郁和记忆的有效性。