Novel Neurogenic Agents as Depression Therapeutics

新型神经源性药物治疗抑郁症

• 批准号: 7053462
• 负责人: KARL K JOHE
• 金额: $ 20.82万
• 依托单位: NEURALSTEM, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7053462
• 关键词: BCL2 gene /protein; antidepressants; apoptosis; axon; behavior test; brain derived neurotrophic factor; brain morphology; cAMP response element binding protein; cell differentiation; cell proliferation; dendrites; dexamethasone; drug design /synthesis /production; gene induction /repression; hippocampus; laboratory mouse; nerve stem cell; neurogenesis; neuropharmacology; nonhuman therapy evaluation; phosphorylation; staurosporine

DESCRIPTION (provided by applicant): Currently available treatments for depression mostly act on increasing the synaptic serotonin levels but do not work universally. Neurogenesis (birth of new neurons) in the adult brain occurs naturally, routinely, and may be functionally important. Inhibition of neurogenesis is thought to be linked to depression and may be the explanation for reduced hippocampal volume seen in patients with major depression. Drugs designed to relieve such inhibition of neurogenesis and to enhance the level of neurogenesis in patients with depression may provide treatment at a structural level and become long-acting, next-generation therapeutics. The objective of this proposal is to determine whether neurogenic activity is critical and sufficient for behavioral efficacy in rodent depression models. By screening small molecule libraries with in vitro and in vivo models of hippocampal neurogenesis, several compounds with in vivo neurogenic activity in mice have been discovered by Neuralstem Inc. Proposed here is a research plan to test these novel neurogenic compounds for efficacy as antidepressants, using in vitro and in vivo models of depression. 3 of the compounds with distinct chemical structures will be tested after chronic oral administration of 4 weeks in 3 mouse models of depression: novelty suppressed feeding, forced swim, and tail suspension tests. In vitro studies will be performed to explore potential mechanism-of-action. Ultimately, a neurogenic compound that is safe, orally available, and working through a novel mechanism for the next generation anti-depressant may result from this study.

描述（由申请人提供）：当前可用的抑郁症治疗方法主要用于提高突触5-羟色胺水平，但不能普遍起作用。成人大脑中的神经发生（新神经元的出生）自然而然地发生，并且在功能上可能很重要。抑制神经发生被认为与抑郁症有关，可能是严重抑郁症患者海马体积减少的解释。旨在缓解这种抑制神经发生并增强抑郁症患者神经发生水平的药物可能会在结构水平上提供治疗，并成为长效的下一代治疗剂。该提案的目的是确定神经源性活性是否至关重要，足以在啮齿动物抑郁模型中行为效率。通过筛选具有海马神经发生的体外和体内模型的小分子库，NeuralStem Inc.在这里发现了几种具有体内神经源活性的化合物。此处提出的研究计划是一项研究计划，旨在测试这些新型神经原发生的化合物，以将功效作为抗抑郁药，并使用In Into in Vivo In Vivo Manderion In Vivo sistion和Into sistion invivo。在3种小鼠抑郁症模型中，慢性口服给药4周后，将测试3种具有不同化学结构的化合物：新颖性抑制了进食，强迫游泳和尾悬浮测试。将进行体外研究以探索潜在的行动机理。最终，这项研究可能会导致一种安全，口服的神经源化合物，并通过新的机制为下一代抗抑制剂而进行。