NEUROCHEMISTRY OF THERAPEUTICS IN PARKINSON'S DISEASE

帕金森病治疗的神经化学

• 批准号: 6610369
• 负责人: ELIZABETH D. ABERCROMBIE
• 金额: $ 20.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610369
• 关键词: 6 hydroxydopamine; Parkinson's disease; antiparkinson drugs; brain disorder chemotherapy; corpus striatum; dihydroxyphenylalanine; dopamine; dopamine antagonists; dopamine receptor; drug adverse effect; drug tolerance; environmental stressor; experimental brain lesion; high performance liquid chromatography; laboratory rat; longitudinal animal study; microdialysis; nervous system disorder diagnosis; neurochemistry; neurons; neuropharmacology; neurotransmitter biosynthesis; nonhuman therapy evaluation; pharmacokinetics; substantia nigra; video recording system

The long-term objective of the proposed research is to understand, at the biochemical level, the basis for the remarkable initial efficacy of L-DOPA as a therapeutic agent for ameliorating the symptoms of Parkinson's disease. Further, we wish to determine the underlying mechanisms that are responsible for the eventual decline in the ability of Parkinsonian patients to tolerate L-DOPA due to unwanted side effects that emerge usually after five to eight years of taking the drug. Despite its shortcomings as a therapeutic agent, L-DOPA remains the most efficacious and widely utilized compound for treating Parkinsonian symptomatology. By better understanding the neurobiology associated with the beneficial as well as the undesirable actions of L-DOPA we will increase our knowledge of this disorder which then ca be applied to the development of improved therapeutic strategies. In addition, such information will contribute to our understanding of both normal and disordered functioning of the basal ganglia. The proposed studies will utilize the 6-OHDA treated rat as an animal model of Parkinson's disease. In vivo microdialysis, a method enabling repeated measurements of extracellular neurotransmitter levels to be conducted in awake animals, will be employed to determine the characteristics of striatal dopamine release after administration of L-DOPA to animals modelling the early stage of Parkinson's disease when the loss of nigrostriatal dopamine is only partial. These data will be compared to previous results obtained in animals modelling the final stage of the disorder when nigrostriatal dopamine degeneration is nearly complete. We also propose to explore the possibility that pharmacological manipulation of the striatal serotonin innervation, which is relatively spared in the late stage of Parkinsonism, may provide means to supply a physiological source of dopamine formed from L-DOPA in severely dopamine-depleted animals and that such an approach may ultimately prove useful for circumventing the problem of emergent, unwanted side effects. Finally, we propose to evaluate the contribution of dopamine acting at basal ganglia sites outside of the primary target region in striatum to the biochemical effects of L-DOPA that occur in this animal model in order to understand the actions of this compound in the context of the basal ganglia circuitry as a whole.

拟议研究的长期目标是了解， 在生化水平上，这是显着的初始的基础 L-DOPA 作为改善疾病的治疗剂的功效 帕金森病的症状。 此外，我们希望确定 负责最终结果的底层机制 帕金森病患者耐受左旋多巴的能力下降 由于通常在五到八点后出现的不良副作用 服用该药物多年。 尽管其作为治疗方法存在缺陷 左旋多巴 (L-DOPA) 仍然是最有效且应用最广泛的药物 用于治疗帕金森病症状的化合物。通过更好 了解与有益相关的神经生物学 以及左旋多巴的不良行为，我们将增加我们的 对这种疾病的了解可以应用到 开发改进的治疗策略。 此外，诸如 信息将有助于我们理解正常的 以及基底神经节功能紊乱。 拟议的 研究将利用 6-OHDA 处理的大鼠作为动物模型 帕金森病。 体内微透析，一种能够 重复测量细胞外神经递质水平 在清醒的动物中进行，将用于确定 给药后纹状体多巴胺释放特征 L-DOPA 用于模拟帕金森病早期阶段的动物 当黑质纹状体多巴胺仅部分丧失时发生疾病。 这些数据将与之前获得的结果进行比较 动物模拟黑质纹状体疾病的最后阶段 多巴胺变性几乎完全。 我们还建议 探讨药物操控的可能性 纹状体血清素神经支配，在晚期相对较少 帕金森病阶段，可能提供一种方法来提供 L-DOPA 形成的多巴胺的生理来源 严重缺乏多巴胺的动物，并且这种方法 最终可能会被证明有助于规避这个问题 紧急的、不需要的副作用。 最后，我们建议评估 多巴胺作用于基底神经节外部部位的贡献 纹状体主要目标区域对生化效应的影响 左旋多巴发生在该动物模型中，以便了解 该化合物在基底神经节中的作用 电路作为一个整体。