Discovery, characterization and preclinical development of pro-neurogenic drugs

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包括精神分裂症在内的多种精神疾病的长期致残方面。与年龄相关的认知能力下降也会使相当一部分人变得虚弱。认知功能障碍与大脑海马体形成功能缺陷有关。齿状回，作为海马体形成的一部分，代表了成人大脑中新神经元定期形成的地方。对实验室小鼠的研究表明，齿状回中新神经元形成的速度受到健康活动的刺激，如轮式跑步、接触丰富的环境和接触社会互动。据推测，能够增强齿状回特异性神经发生的药物可能对患有认知缺陷的患者有益。在过去的三年里，撰写这一申请的研究人员进行了一项公正的体内筛选，以确定能够刺激海马神经发生的药物样化学物质。通过这些努力，我们发现了八种不同的神经原性化合物。其中一种化合物已被发现是口服生物可利用的，具有良好的半衰期，能够穿过血脑屏障，并且在以最小治疗剂量的10倍剂量给药数月后没有毒性。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生成和存活。这八种化合物的假定功效正在研究人员实验室特有的精神分裂症动物模型中。同样，生化方法将被用来鉴定尽可能多的8种前神经源性化合物的分子靶点。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方案提供基础。

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.