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，注意力和决策的认知缺陷代表了包括精神分裂症在内的许多形式的多种形式的长期致残的方面。与年龄相关的认知能力下降也可能使人衰弱到大部分人口。认知功能障碍与大脑海马形成功能不足有关。作为海马形成的一部分，齿状回的位点代表了成人大脑定期形成新神经元的部位。实验室小鼠的研究表明，齿状回的新神经元形成的速率受到健康活动，例如驾驶，进入丰富的环境以及进入社交相互作用的健康活动。假设特异性增强齿状回特异性神经发生的药理学剂可能使患有认知缺陷的患者受益。在过去的三年中，创作该应用的研究人员进行了一个公正的体内筛查，以识别能够刺激海马神经发生的药物样化学物质。这些努力导致发现了八种独特的促核化合物。这些化合物之一被发现是口服生物利用物，具有良好的半衰期，能够越过血脑屏障，并且在10倍以10倍升级为10倍以最小的治疗剂量下进行了多个月给药后没有毒性。详细的研究表明，这种最先进的化合物增强了海马神经元的出生和存活。在研究人员实验室独有的精神分裂症模型中，正在研究这八种化合物的推定功效。同样，将采用生化方法来识别尽可能多的八种促神神经化合物的分子靶标。希望这项工作将为患有与精神疾病相关的认知缺陷的患者发现新的治疗选择提供基础。 公共卫生相关性：学习，记忆，注意力和决策的叙事缺陷代表了许多形式的精神疾病的长期致残方面以及与年龄相关的智力下降。认知功能障碍与大脑海马形成功能不足有关。 McKnight和Pieper试图通过药物剂来增强海马功能，从而刺激大脑该区域中新神经元的出生和功能掺入。我们的目标是为患有认知缺陷的患者发现新的治疗选择提供基础。