THERAPEUTIC POTENTIAL OF NEUROTROPHINS IN ALZHEIMERS

神经营养素在阿尔茨海默病中的治疗潜力

• 批准号: 2051700
• 负责人: FRANZ F HEFTI
• 金额: $ 41.24万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2051700
• 关键词: Alzheimer's disease; neural degeneration; neuroprotectants; neurotrophic factors

Summary: Alzheimer's disease (AD) is associated with degeneration changes and loss of various specific populations of neurons in the brain. Since neurotrophic factors regulate survival and differentiated functions of neurons, they may provide avenues for the development of effective treatment for AD. By preventing or attenuating neuronal degeneration, neurotrophic factors may slow down or stop the progression of the disease and associated cognitive disturbances. Based on its ability to prevent degenerative changes of cholinergic neurons induced by experimental lesions in rats and monkeys, nerve growth factor (NGF) is presently considered as experimental treatment for AD. The value of NGF in the treatment of AD is limited by its selectivity for forebrain cholinergic neurons. NGF homologs, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), forming the family of neurotrophins, affect many populations of brain neurons. The analysis of their neurotrophic actions is ongoing. They appear to have different, but partially overlapping spectra of activity on select populations of central neurons. Aiming at identifying the most useful neurotrophin molecules, we propose to prepare neurotrophins, neurotrophin mutants, modified neurotrophins, as well as novel neurotrophic factors for this program project. The new molecules will be characterized initially in receptor assays and in cell culture assays. Biologically active molecules selected by the in vitro assays will then be tested in vivo in rat brain lesion models mimicking degenerative changes occurring in AD brains. Models of neurodegeneration to be used include septo-hippocampal cholinergic and GABAergic neurons after fimbrial transection, cortico- hippocampal neurons after transections of the angular bundle, and thalamo-cortical neurons after cingulotomy. Two additional projects are proposed. To assess the therapeutic potential of neurotrophins, we plan to measure the responsiveness of brain tissue to neurotrophins using a novel ex vivo assay. We propose to further analyze the therapeutic potential of the small molecules K-252a and K-252b, compounds earlier shown to potentiate the action of NT-3. It is hoped that the studies will lead to the identification of neurotrophin variants, other neurotrophic factors or small molecules most useful for further development as therapeutics in Alzheimer's disease. The program project joins established academic and industrial scientists with a record of previous collaboration in the pharmacological exploitation of neurotrophic factors for developing effective treatment for AD and cognitive diseases.

摘要：阿尔茨海默病（AD）与退化有关 大脑中各种特定神经元群体的变化和丢失。 由于神经营养因子调节存活和分化功能 神经元，他们可能提供发展有效的途径， 治疗AD。 通过预防或减弱神经元变性， 神经营养因子可以减缓或阻止疾病的进展 以及相关的认知障碍 基于其预防能力 实验性胆碱能神经元退行性改变 神经生长因子（NGF）是一种神经生长因子， 被认为是AD的实验性治疗。 神经生长因子的价值 AD的治疗受限于其对前脑胆碱能的选择性， 神经元 神经生长因子同源物，脑源性神经营养因子（BDNF）， 神经营养因子-3（NT-3）和神经营养因子-4/5（NT-4/5），形成神经营养因子家族 神经营养因子，影响许多群体的大脑神经元。 分析 它们的神经营养作用正在进行。 他们似乎有不同的， 但部分重叠的活性谱上选择的人口 中枢神经元 目的是鉴定最有用的神经营养因子 分子，我们建议制备神经营养因子，神经营养因子突变体， 修饰的神经营养素，以及新的神经营养因子， 程序项目。 新分子的特征将在 受体测定和细胞培养测定。 生物活性 然后将在体内测试通过体外试验选择的分子 模拟AD退行性改变的大鼠脑损伤模型 大脑 使用的神经变性模型包括隔-海马 切断海马伞后，胆碱能和GABA能神经元，皮质- 切断角束后的海马神经元，以及 扣带回切开术后的丘脑-皮质神经元。 另外两个项目是 提出了 为了评估神经营养因子的治疗潜力，我们计划 用一种神经营养因子来测量脑组织对神经营养因子的反应， 新的离体测定。 我们建议进一步分析治疗 小分子K-252 a和K-252 b的潜力， 显示增强NT-3的作用。 希望这些研究 将导致神经营养因子变体的鉴定，其他 神经营养因子或小分子，最适用于进一步 作为阿尔茨海默病的治疗方法。 该计划项目 加入了学术界和工业界的科学家， 以前在药理学开发方面的合作 神经营养因子用于开发AD的有效治疗， 认知疾病