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Efficacy of a Novel Neuroprotective Compound in Nonhuman Primate

新型神经保护化合物对非人类灵长类动物的功效

基本信息

批准号：
8904994
负责人：
Melissa Dawn Bauman
金额：
$ 3.91万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8904994
关键词：
Adult Adverse effects Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyotrophic Lateral Sclerosis Anatomy Animal Model Animals Anxiety Disorders Apoptosis Apoptotic Basic Science Behavior Binding Biochemistry Bone Marrow Brain Brain Diseases Carbazoles Cell Death Cell Proliferation Cell Survival Cessation of life Chemicals Cognition Collaborations Colon Complex Data Development Disease Disease model Drug Kinetics Dyes Emotions Evaluation Exposure to Fluorine Funding Genetic Models Goals Heart Hela Cells Hippocampus (Brain)Histamine Receptor Binding Histologic Human Impaired cognition Kidney Laboratories Learning Life Literature Liver Lung Macaca mulatta Medical center Membrane Potentials Mental Depression Mitochondria Modeling Molecular Monitor Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neuroprotective Agents Neurosciences Newborn Infant Oral Administration Parkinson Disease Patients Performance Peripheral Pharmaceutical Preparations Physiology Preparation Primate Diseases Primates Property Proxy Rat-1 Rattus Relative (related person)Request for Applications Research Rodent Model Role Safety Small Intestines Spinal Cord Spleen Structure Structure-Activity Relationship Therapeutic Therapeutic Effect Tissues Toxic effect Translating Translations Variant Wild Type Mouse Work aged analog carbazole cognitive function cost effective design drug development granule cell hydroxyl group improved in vivo meetings member mitochondrial membrane morris water maze neural precursor cell neurogenesis neuron loss neuroprotection neuropsychiatry nonhuman primate novel novel therapeutic intervention pre-clinical prevent programs protective effect protective efficacy scaffold screening standard measure treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Due to a profound lack of treatment options for neuropsychiatric disease, there is a critical need to facilitate the translation of findings from basic neuroscience to new treatments for patients. Through an in vivo screen conducted in living mice, a biologically active aminopropyl carbazole, designated P7C3, was identified with potent proneurogenic and neuroprotective properties. A multi-year structure-activity-relationship study on this chemical scaffold has enabled optimization of potency and efficacy, while minimizing real and perceived liabilities for drug development. The P7C3 class of molecules stabilizes mitochondrial membrane potential and protects neurons from cell death. Significant protective efficacy of P7C3 and it's more potent and efficacious variant, P7C3A20, has now been demonstrated in animal models of aging, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. A new challenge is to provide additional evidence that these compounds could be beneficial to the human brain. An initial step to meet this challenge is to demonstrate that the most effective of these compounds (P7C3A20) has a proneurogenic and/or protective effect in the nonhuman primate brain. Human brain disorders are defined by changes in complex human behaviors (i.e., cognition, emotion etc.), and evaluation of the therapeutic effects of neuroprotective compounds may ultimately benefit from studies in animal species that are more closely related to humans than are mice. Moreover, the literature is replete with examples of drugs that work well in mice but are not therapeutically beneficial in humans. Rhesus macaques (Macaca mulatta) provide a useful proxy for efficacy in the human, as they demonstrate many features of human physiology, anatomy and behavior. Rhesus monkeys are thus ideal for studying a variety of complex human brain disorders. However, before we can begin to explore the therapeutic potential of the P7C3 class of molecules in sophisticated nonhuman primate diseases models, we must first establish a neuroprotective role for the P7C3 class of molecules in the primate brain. Here, we propose quantification of nonhuman primate hippocampal neurogenesis as a function of exposure to P7C3A20, in order to provide a rapid, cost effective and straightforward means of assessing efficacy of neuroprotection in the rhesus monkey. Preclinical proof of principle in a nonhuman primate could provide an opportunity to translate basic science into a new therapeutic approach for patients suffering from both neuropsychiatric and neurodegenerative diseases involving diminished hippocampal neurogenesis and/or broader neurodegeneration.

描述（由申请人提供）：由于严重缺乏神经精神疾病的治疗选择，迫切需要促进将基础神经科学的发现转化为患者的新治疗方法。通过在活体小鼠中进行的体内筛选，鉴定出具有生物活性的氨丙基咔唑，命名为P7C3，具有有效的前神经发生和神经保护特性。对这种化学支架进行的多年结构-活性-关系研究已经能够优化效力和功效，同时最大限度地减少药物开发的真实的和感知的责任。P7C3类分子稳定线粒体膜电位并保护神经元免于细胞死亡。P7C3及其更有效的变体P7C3A20的显著保护功效现已在衰老、阿尔茨海默病、帕金森病和肌萎缩性侧索硬化症的动物模型中得到证实。一个新的挑战是提供更多的证据证明这些化合物可能对人类大脑有益。迎接这一挑战的第一步是证明这些化合物中最有效的化合物（P7C3A20）在非人灵长类动物脑中具有前神经发生和/或保护作用。人类大脑疾病是由复杂的人类行为的变化定义的（即，认知、情感等），神经保护化合物的治疗效果的评估最终可能会受益于对与人类比小鼠关系更密切的动物物种的研究。此外，文献中充满了对小鼠有效但对人类无效的药物的例子。恒河猴（Macaca mulatta）提供了一个有用的代理人在人类中的疗效，因为它们表现出许多人类生理学，解剖学和行为的特征。因此，恒河猴是研究各种复杂的人类大脑疾病的理想动物。然而，在我们开始探索P7C3类分子在复杂的非人灵长类动物疾病模型中的治疗潜力之前，我们必须首先确定P7C3类分子在灵长类动物大脑中的神经保护作用。在这里，我们提出了定量的非人灵长类动物海马神经发生作为暴露于P7C3A20的函数，以提供一种快速，具有成本效益和直接的方法来评估恒河猴神经保护的功效。在非人灵长类动物中的临床前原理证明可以提供一个机会，将基础科学转化为一种新的治疗方法，用于患有神经精神和神经退行性疾病的患者，这些疾病涉及海马神经发生减少和/或更广泛的神经退行性变。