Discovery, characterization and preclinical development of pro-neurogenic drugs

促神经源性药物的发现、表征和临床前开发

• 批准号: 8101261
• 负责人: STEVEN L MCKNIGHT
• 金额: $ 124.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101261
• 关键词: Adult; Animal Model; Attention; Bioavailable; Biochemical; Birth; Blood - brain barrier anatomy; Brain; Brain region; Chemicals; Cognitive; Cognitive deficits; Decision Making; Development; Dose; Environment; Goals; Half-Life; Hippocampal Formation; Hippocampus (Brain); Human; Impaired cognition; Laboratories; Laboratory mice; Learning; Link; Memory; Mental disorders; Methods; Molecular Target; Neurons; Patients; Pharmaceutical Preparations; Population; Psyche structure; Research Personnel; Running; Schizophrenia; Site; Social Interaction; Therapeutic; Toxic effect; Work; age related; base; dentate gyrus; in vivo; mental age; neurogenesis; pre-clinical; public health relevance

DESCRIPTION (provided by applicant): Cognitive deficits in learning, memory, attention and decision-making represent chronically disabling aspects of many forms of mental illness, including schizophrenia. Age-related decline in cognitive abilities can also be debilitating to a substantial fraction of the human population. Cognitive dysfunction has been linked to deficient functioning of the hippocampal formation of the brain. The dentate gyrus, as part of the hippocampal formation, represents a site where new neurons are formed on a regular basis in the adult brain. Studies in laboratory mice have shown that the rate of new neuron formation in the dentate gyrus is stimulated by healthy activities such as wheel running, access to an enriched environment, and access to social interaction. It is hypothesized that pharmacological agents that specifically augment dentate gyrus-specific neurogenesis may benefit patients suffering from cognitive deficits. Over the past three years the investigators authoring this application have conducted an unbiased in vivo screen to identify drug-like chemicals capable of stimulating hippocampal neurogenesis. These efforts have led to the discovery of eight distinct, pro-neurogenic compounds. One of these compounds has been found to be orally bioavailable, endowed with a favorable half life, capable of crossing the blood brain barrier, and devoid of toxicity following multi-month administration at a level 10X the minimal therapeutic dose. Detailed studies have shown that this most advanced compound enhances both the birth and survival of hippocampal neurons. The putative efficacies of these eight compounds are being studied in an animal model of schizophrenia unique to the laboratory of the investigators. Likewise, biochemical methods will be employed to identify the molecular targets of as many of the eight pro-neurogenic compounds as possible. It is hoped that this work will provide a basis for the discovery of new treatment options for patients suffering from cognitive deficits associated with mental illness. PUBLIC HEALTH RELEVANCE: Narrative Deficits in learning, memory, attention and decision-making represent chronically disabling aspects of many forms of mental illness and age-related decline in mental capacity. Cognitive dysfunction has been linked to deficient functioning of the hippocampal formation of the brain. McKnight and Pieper seek to augment hippocampal functioning through pharmacologic agents that stimulate the birth and functional incorporation of new neurons in this region of the brain. Our goal is to provide a basis for the discovery of new treatment options for patients suffering from cognitive deficits.

描述(由申请人提供)：学习、记忆、注意力和决策方面的认知缺陷代表了许多形式的精神疾病的慢性致残方面，包括精神分裂症。与年龄相关的认知能力下降也可能使相当一部分人变得虚弱。认知功能障碍与大脑的海马体结构功能缺陷有关。齿状回是海马结构的一部分，代表着成年大脑中新神经元定期形成的地方。在实验室小鼠的研究表明，轮子跑、接触丰富的环境和社交等健康活动刺激了齿状回新神经元的形成速度。据推测，专门增强齿状回特异性神经发生的药物可能会使患有认知缺陷的患者受益。在过去的三年里，编写这一应用程序的研究人员进行了一项无偏见的活体筛选，以识别能够刺激海马神经发生的类药物化学物质。这些努力已经导致发现了八种不同的、有利于神经发生的化合物。这些化合物中的一种已被发现具有口服生物利用度，具有良好的半衰期，能够通过血脑屏障，在最小治疗量的10倍水平上连续数月给药没有毒性。详细的研究表明，这种最先进的化合物可以促进海马神经元的诞生和存活。这八种化合物的假定有效性正在研究人员实验室特有的精神分裂症动物模型中。同样，将使用生化方法来识别尽可能多的八种促神经原化合物的分子靶标。希望这项工作将为发现与精神疾病相关的认知缺陷患者的新治疗选择提供基础。 公共卫生相关性：学习、记忆、注意力和决策方面的叙述缺陷代表了许多形式的精神疾病的长期残疾方面以及与年龄相关的精神能力下降。认知功能障碍与大脑的海马体结构功能缺陷有关。麦克奈特和派珀试图通过药物来增强海马体的功能，这些药剂可以刺激大脑这一区域新神经元的诞生和功能整合。我们的目标是为发现认知缺陷患者的新治疗选择提供基础。