GM1 CORRECTS NEUROTRANSMITTER DEFICITS IN AGED BRAIN

GM1 纠正老年大脑中神经递质的缺陷

• 批准号: 6168124
• 负责人: MARIA H NEFF
• 金额: $ 22.04万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6168124
• 关键词: Parkinson's disease; aging; brain metabolism; dopamine; enzyme activity; gangliosidosis GM1; laboratory rat; mental disorder chemotherapy; methylphenyltetrahydropyridine; nervous system disorder chemotherapy; neural transmission; neurotrophic factors; nonhuman therapy evaluation; protein tyrosine kinase

DESCRIPTION (Taken from applicant's abstract): This proposal has 2 well defined goals: to explore the consequences of administering GM1 ganglioside on brain neurotransmission in aged rats, and to determine the mechanism(s) for the trophic action of GM1 in vivo. The main focus will be on the dopaminergic system. Systemic administration of GM1, a normal constituent of the membranes of brain, was previously shown to enhance cholinergic neurochemical and morphological markers in the brain of aged rats. The first aim is to determine the effects of GM1 on dopaminergic neurochemical deficits in the brain of aged animals, and evaluate whether the response is stable when treatment is discontinued. This includes the following: to elucidate whether cholinergic and dopaminergic function that deteriorates with age can be prevented or delayed by administering GM1 to mature animals; to study by immunohistochemistry-autoradiography whether GM1 improves the number and/or morphology of the neurons of interest, and whether GM1 can induce neuronal sprouting; to dissect the possible relationship between the various neurotransmitter deficits and cognitive and motor function in aged animals; to explore whether enhancement of neurochemical and morphological markers by GM1 includes behavioral (cognitive, motor) improvement and investigate the possible relationship(s) with specific neurotransmitter change(s). The second specific aim is to establish the mechanism(s) for the trophic action of GM1 in the brain in vivo. This includes the following: to establish an in situ system to investigate the GM1-induced tyrosine phosphorylation of Trk in brain slices from young and aged animals; to determine the pharmacology and specificity of the response; to determine whether the GM1-induced tyrosine phosphorylation of Trk initiates the same signal cascade as the neurotrophins; to explore the GM1/ neurotrophin synergism at the molecular level. To investigate whether acute or chronic administration of GM1 induces tyrosine phosphorylation of Trk in vivo, the possible enhancement of the neurotrophin-induced autophosphorylation of Trk, and the effect of aging on the response(s).

描述（取自申请人的摘要）：该提案有2个井 定义目标：探索管理GM1的后果 在老年大鼠的脑神经传递上的神经节剂，并确定 GM1在体内营养作用的机制。 主要重点 将在多巴胺能系统上。 GM1的系统给药 以前证明了大脑膜的正常成分 增强大脑中的胆碱能神经化学和形态标记 老鼠。 第一个目的是确定GM1对 老年动物大脑中的多巴胺能神经化学缺陷， 当治疗停产时，评估反应是否稳定。 这包括以下内容：阐明胆碱能和 可以预防随着年龄的年龄恶化的多巴胺能功能或 通过将GM1给予成熟动物延迟；学习 免疫组织化学 - AutorAdiography是否GM1是否改善了数量 和/或感兴趣的神经元的形态，以及GM1是否可以诱导 神经元发芽；剖析 各种神经递质缺陷以及认知和运动功能 老年动物；探索神经化学和 GM1的形态标记包括行为（认知，运动） 改善并调查可能与特定的关系 神经递质变化。 第二个具体目的是建立营养的机制 GM1在体内的作用。 这包括以下内容： 建立一个原位系统来研究GM1诱导的酪氨酸 来自年轻动物和老年动物的脑切片中TRK的磷酸化；到 确定反应的药理学和特异性；确定 GM1诱导的TRK酪氨酸磷酸化是否启动 与神经营养蛋白相同的信号级联；探索GM1/ 神经营养蛋白在分子水平上的协同作用。 调查是否 GM1的急性或慢性给药可诱导酪氨酸磷酸化 trk in Vivo，神经营养蛋白诱导的可能增强 TRK的自磷酸化以及衰老对响应的影响。