GM1 CORRECTS NEUROTRASMITTER DEFICITS IN AGED BRAIN

GM1 纠正老年大脑中神经递质的缺陷

• 批准号: 2655793
• 负责人: MARIA H NEFF
• 金额: $ 10万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2655793
• 关键词: acetylcholine; aging; brain disorder chemotherapy; brain metabolism; cholinergic agents; corpus striatum; gangliosides; hippocampus; laboratory rat; neural degeneration; neuropharmacology; neurotrophic factors

Aging is associated with a loss of brain neurotransmitter function which apparently is the substrate for a diverse constellation of age-associated symptoms. Systemic administration of GM1 ganglioside, a normal constituent of the membranes of the brain, enhances cholinergic neurochemical and morphological markers in the brain of aged (22-24 month old) rats. We now provide evidence that GM1, also, improves the neurochemistry and morphology of dopaminergic neurons in the aged brain. The improvement of cholinergic and dopaminergic neuronal activity is accompanied by enhanced cognitive and motor performance. GM 1-induced recovery of function in aged animals is long-lasting, as both neurochemical and behavioral enhancement is maintained for 15 days after the discontinuation of GM1 treatment. In many aspects, the trophic actions of the GM1 in various systems resemble those of the neurotrophins. Based on these observations, we speculated that GM1 might exert its trophic effects, in part, by interacting with the neurotrophins. Recently, this notion has been supported by observations that NGF and GM1 display pharmacological synergism, and that in cell lines GM1 induces tyrosine phosphorylation of the NGF receptor TrkA. We provide evidence that GM1 is capable of inducing Trk tyrosine phosphorylation in brain tissues in situ and in vivo. Interestingly, GM1 tyrosine phosphorylation of Trk is maintained in aged animals. Our general goals are: (1) to continue exploring the consequences of administering GM1 on brain neuronal neurochemistry, morphology and behavior in aged animals; and (2) to investigate the molecular mechanism(s) of the GM1 neurotrophic action. In this regard, dopaminergic and serotonergic neurons of aged brain will be studied, as they are important contributors for the pathogenesis of age-associated motor, cognitive and mental disorders. The interaction of GM1 with other neurotrophins, BDNF and NT-3, will be investigated, and, the role of GM1 for Trk neurotrophin receptor tyrosine phosphorylation and signaling pathways will be explored. Understanding the mechanism(s) underlying the neurotrophic actions of GM1 in vivo will validate the utility of the ganglioside as a putative therapeutic modality for treating/preventing age-associated symptomatology. GM1 has major therapeutic advantages over the peptide neurotrophic factors; it can be administered systemically and its action is long-lasting. More importantly, GM1 can serve as a model molecule for the synthesis of neurotrophic drugs with better bioavailability and efficacy, and with limited side effects.

衰老与脑神经递质功能的丧失有关 显然是与年龄相关的多样化星座的底物 症状。 GM1神经节的全身给药，一种正常成分 在大脑的膜上增强胆碱能神经化学和 年龄（22-24个月大）大鼠大脑的形态标记。我们现在 提供了GM1的证据，还可以改善神经化学和 老年大脑多巴胺能神经元的形态。改进 胆碱能和多巴胺能神经元活性伴随着增强 认知和运动性能。 GM 1诱导的老年功能恢复 动物是持久的，因为神经化学和行为增强 在停用GM1治疗后，将维持15天。在 许多方面，GM1在各种系统中的营养作用类似 神经营养蛋白的那些。基于这些观察，我们推测 GM1可能通过与 神经营养蛋白。最近，这一概念得到了观察的支持 NGF和GM1表现出药理学的协同作用，并且在细胞系中 GM1诱导NGF受体TRKA的酪氨酸磷酸化。我们提供 GM1能够诱导TRK酪氨酸磷酸化的证据 原位和体内脑组织。有趣的是，GM1酪氨酸 TRK的磷酸化维持在老年动物中。我们的一般目标 为：（1）继续探索在 老年动物的脑神经元神经化学，形态和行为； （2）研究GM1神经营养的分子机制 行动。在这方面，老化的多巴胺能和血清素能神经元 将研究大脑，因为它们是重要的贡献者 年龄相关运动，认知和精神障碍的发病机理。这 GM1与其他神经营养蛋白BDNF和NT-3的相互作用将是 研究了，GM1在TRK神经营养蛋白受体酪氨酸中的作用 将探索磷酸化和信号通路。了解 GM1在体内的神经营养作用的基础机制将 验证神经节苷脂作为推定的治疗方式 用于治疗/预防与年龄相关的症状学。 GM1有专业 比肽神经营养因素具有治疗优势；可以 系统地管理及其作用是长期的。更多的 重要的是，GM1可以用作合成的模型分子 具有更好的生物利用度和功效的神经营养药物，并且 有限的副作用。