A novel estrogen modulator for the treatment of Alzheimer's disease

一种用于治疗阿尔茨海默病的新型雌激素调节剂

• 批准号: 9898288
• 负责人: JOSEPH F QUINN
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898288
• 关键词: Adverse effects; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyloidosis; Animals; Anti-Inflammatory Agents; Antioxidants; Attenuated; Biochemical; Biochemical Markers; Biological Assay; Biological Models; Blood Coagulation Factor; Blood coagulation; Brain; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Coagulation Process; Data; Enzyme-Linked Immunosorbent Assay; Estrogens; Evaluation; Event; Feminization; Future; Genetic Engineering; Genetically Engineered Mouse; Goals; Gonadal Steroid Hormones; Healthcare Systems; Hippocampus (Brain); Histologic; Hormones; Human; Immunohistochemistry; Inbred C57BL Mice; Investigation; Laboratories; Lesion; Malignant Neoplasms; Measurement; Mediating; Memory; Methods; Mitochondria; Molecular; Morbidity - disease rate; Morphology; Mus; Mutation; Neurons; Oncogenic; Ovariectomy; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Postmenopause; Prevention; Prevention therapy; Property; Protocols documentation; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Safety; Series; Signal Pathway; Signal Transduction; Synapses; Testing; Tg2576; Transgenic Mice; Transgenic Organisms; Validation; Vertebral column; Wild Type Mouse; Woman; aging brain; base; behavior test; clinical development; cost; density; estrogenic; experimental study; human subject; in vivo; inhibitor/antagonist; interest; male; men; metal chelator; morris water maze; mouse model; neuroprotection; neurotoxic; neurotoxicity; normal aging; novel; novel therapeutics; prevent; protective effect; protein aggregation; reproductive organ; response; side effect; spatial memory

A number of studies have shown that the sex hormone, estrogen, has favorable or “neurotrophic” effects on neuronal cells in the brain. Unfortunately, clinical trials using estrogen revealed unacceptable side effects, including increased risk of blood clots and hormone- sensitive cancers. Moreover, estrogen is not practical for use in men, because it promotes unwanted physical changes and feminizing effects; consequently, estrogen has been abandoned as a treatment for AD. As an alterative strategy, the current study will test a novel drug called “STX”, which has the favorable neurotrophic effects of estrogen without its unwanted side effects. Preliminary studies indicate that STX protects neuronal cells against Alzheimer’s-associated toxic responses and can be safely given to mice as they age. The overall goal is to determine if STX has potential for treating Alzheimer’s disease in human patients. This drug will be tested first on brain neuronal cells grown in a dish under conditions that mimic specific aspects of Alzheimer’s disease, with the goal of identifying the molecular pathways that control its protective responses. The drug will then will be tested in normal aging mice (to confirm its safety), and in mice that have been genetically engineered to develop Alzheimer-type changes in the brain. Established protocols will be used to carefully assess the effects of STX on memory function, neuronal damage, and brain lesions associated with Alzheimer’ Disease. These studies will integrate behavioral tests of spatial memory, immunohistochemical methods to quantify neuronal damage, and biochemical assays to quantify protein aggregation. Concurrently, the molecular pathways identified in cultured neuronal cells will be validated in the brains of treated animals. Successful completion of these experiments will provide the framework for advancing STX toward clinical trials.

许多研究表明，性激素，雌激素，具有良好的或 “神经营养”对大脑中的神经细胞的影响。不幸的是，使用雌激素的临床试验 暴露出不可接受的副作用，包括增加血栓和激素的风险- 敏感的癌症。此外，雌激素在男性身上并不实用，因为它能促进 不想要的身体变化和女性化的影响；因此，雌激素 作为治疗阿尔茨海默病的药物被放弃。 作为一种替代策略，目前的研究将测试一种名为“STX”的新药，它具有 雌激素具有良好的神经营养作用，无不良副作用。初步研究 表明STX保护神经细胞免受阿尔茨海默病相关的毒性反应和 可以安全地给小鼠随着年龄的增长而服用。总体目标是确定STX是否具有潜力 用于治疗人类患者的阿尔茨海默病。 这种药物将首先在培养皿中生长的脑神经元细胞上进行测试，条件是模拟 阿尔茨海默病的特定方面，目的是确定 控制它的保护性反应。然后，该药物将在正常衰老的小鼠身上进行测试(到 确认它的安全性)，以及在经过基因工程改造而患上阿尔茨海默病的小鼠身上 大脑的变化。已建立的方案将用于仔细评估STX的影响 与阿尔茨海默病相关的记忆功能、神经元损伤和脑损伤。 这些研究将结合空间记忆的行为测试、免疫组织化学方法 以量化神经元损伤，以及生化分析以量化蛋白质聚集。 同时，在培养的神经细胞中确定的分子通路将在 经过处理的动物的大脑。这些实验的成功完成将为 将STX推向临床试验的框架。