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，具有有利的或 对脑中神经元细胞的“神经营养”作用。不幸的是，使用雌激素的临床试验 显示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，雌激素在男性中使用是不实际的，因为它促进 不必要的身体变化和女性化的影响;因此，雌激素一直是 被放弃作为AD的治疗方法。 作为一种替代策略，目前的研究将测试一种名为“STX”的新药， 雌激素有利的神经营养作用，而没有不必要的副作用。初步研究 表明STX保护神经元细胞免受阿尔茨海默病相关毒性反应， 可以安全地给老鼠服用。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细胞上进行测试， 阿尔茨海默病的具体方面，目的是确定分子途径， 控制其保护性反应。然后将在正常衰老的小鼠中测试该药物（以 证实其安全性），并在小鼠中进行了基因工程改造， 大脑的变化。已建立的协议将被用来仔细评估STX的影响 记忆功能、神经元损伤和与阿尔茨海默病相关的脑损伤。 这些研究将整合空间记忆行为测试、免疫组织化学方法 来量化神经元损伤，以及生化分析来量化蛋白质聚集。 同时，在培养的神经元细胞中鉴定的分子途径将在 处理动物的大脑。这些实验的成功完成将提供 将STX推向临床试验的框架。