Cdk-mediated striatal neuroadaptation in parkinsonism

Cdk 介导的帕金森病纹状体神经适应

• 批准号: 6899006
• 负责人: JUSTIN D OH-LEE
• 金额: $ 19.15万
• 依托单位: CENTRAL MICHIGAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899006
• 关键词: 6 hydroxydopamine; Parkinson' s disease; RNA interference; abnormal involuntary movement; behavior test; biological signal transduction; corpus striatum; cyclin dependent kinase; enzyme activity; glutamate receptor; glutamates; immunocytochemistry; immunoprecipitation; kinase inhibitor; laboratory rat; levodopa; neural plasticity; neuropathology; neurotransmitter transport; phosphorylation; protein kinase A; protein protein interaction; substantia nigra; western blottings

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disorder currently afflicting nearly over one million Americans. Initially, treatment with levodopa (L-DOPA) or a direct dopamine agonist ordinarily confers substantial clinical benefit. Within a few years, however, repetitive administration of these drugs to PD patients ultimately leads to development of disabling motor response complications. Current evidence suggests that these response alterations involve activation of striatal signal transduction cascades causing upregulation of corticostriatal glutamatergic synaptic transmission which in turn modifies striatal output in ways that compromise motor behavior. FosB-mediated activation of cycline-dependent kinase 5 (Cdk5) has been increasingly implicated in the neuroadaptive mechanisms related to repeated psychostimulant administration in drug addiction. To elucidate molecular mechanisms that underlie the pathogenesis of motor response occurring with chronic L-DOPA treatment of parkinsonian animals, the time course of response shortening and the appearance of Abnormal Involuntary Movements (AIMs) is evaluated in relation to change in striatal Cdk5 and glutamatergic signaling in 6-hydroxydopamine lesioned rats. The striatal tissue from these animals is also evaluated for these biochemical changes by using Western blot, Immunoprecipitation and immunohistochemical analyses. The functional significance of striatal Cdk5 activation is then determined by assessing the ability of Cdk5 antisense and inhibitors to affect both the biochemical and motor response changes associated with chronic dopaminomimetic treatment and its subsequent withdrawal. Findings from the proposed studies can provide more accurate understanding of molecular mechanisms underlying striatal neuroadaptive plasticity contributing to the pathogenesis of LDOPA- induced genesis of maladaptive motor complications in advanced PD, and suggest novel approaches to safer and more effective therapy of extrapyramidal motor dysfunction and other dopamine disease states.

描述（由申请人提供）：帕金森氏病（PD）是一种神经退行性疾病，目前遭受了近100万美国人的困扰。 最初，用左旋多巴（L-DOPA）或直接多巴胺激动剂治疗通常赋予了可观的临床益处。然而，在几年之内，这些药物对PD患者的重复施用最终导致致残运动反应并发症的发展。当前的证据表明，这些响应改变涉及激活纹状体信号转导级联反应，从而导致皮质纹状体谷氨酸能突触传播上调，从而以损害运动行为的方式改变了纹状体输出。 FOSB介导的依赖环素激酶5（CDK5）的激活与与药物成瘾中反复的心理刺激施用有关的神经适应机制越来越多。为了阐明帕金森氏症动物的慢性L-DOPA治疗发生的运动反应发病机制的分子机制，评估了反应缩短的时间疗程和异常非自愿运动的出现（AIMS）与纹状体CDK5和6-Hydroxydroxydopaminedopamine的6-甲状腺素lipatemine ratsionepamineiparamine rats的变化有关。还通过使用蛋白质印迹，免疫沉淀和免疫组织化学分析来评估这些动物的纹状体组织。然后，通过评估CDK5反义和抑制剂影响与慢性多巴胺映射治疗以及随后退出有关的生化和运动反应变化的能力来确定纹状体CDK5激活的功能显着性。提出的研究的结果可以更准确地了解纹状体神经适应性可塑性的分子机制，这有助于高级PD中LDOPA诱导的疾病疾病的发病机理，并提出新颖的方法对更安全和更有效的运动型运动型运动型疾病和其他dopamamine病态的新型方法进行了新的方法。