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，这是显着初始的基础 L-DOPA作为治疗剂的功效，以改善 帕金森氏病的症状。 此外，我们希望确定 最终负责的基本机制 帕金森患者耐受L-DOPA的能力下降 由于不必要的副作用，通常在五到八个之后出现 多年服用药物。 尽管缺点是治疗性的 特工，l-dopa仍然是最有效和广泛使用的 治疗帕金森氏症状学的化合物。好的 了解与有益的神经生物学 以及L-DOPA的不良行为，我们将增加我们的 对这种疾病的了解，然后将其应用于 制定改进的治疗策略。 另外，这样的 信息将有助于我们对两个正常的理解 和基底神经节的功能无序。 提议 研究将利用6-OHDA处理的大鼠作为动物模型 帕金森氏病。 体内微透析，一种启用的方法 重复测量细胞外神经递质水平 在清醒的动物中进行，将被用来确定 给药后纹状体多巴胺释放的特征 l-dopa对帕金森氏症早期阶段的动物建模 疾病当骨纹状体多巴胺的丧失只是部分。 这些数据将与以前获得的结果进行比较 当骨纹时，动物对疾病的最后阶段进行建模 多巴胺变性几乎完成。 我们还建议 探索药理学操纵的可能性 纹状体5-羟色胺神经支配，在晚期相对幸免 帕金森主义的阶段，可以提供提供的手段 由L-DOPA形成的多巴胺的生理来源 严重多巴胺的动物，这种方法 最终可能被证明可用于规避问题 出现，不必要的副作用。 最后，我们建议评估 多巴胺在基底神经节地点作用的贡献 纹状体中主要目标区域的生化作用 为了理解该动物模型中发生的L-DOPA 这种化合物在基底神经节的背景下的作用 整个电路。