Pathogenesis And Treatment Of Neurodegenerative Disease

神经退行性疾病的发病机制和治疗

• 批准号: 7143815
• 负责人: MARK A HALLETT
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7143815
• 关键词: AMPA receptors; NMDA receptors; Parkinson' s disease; abnormal involuntary movement; adenosine; alpha adrenergic receptor; alpha antiadrenergic agent; antiparkinson drugs; clinical research; corpus striatum; dopamine agonists; drug interactions; human subject; human therapy evaluation; inhibitor /antagonist; levodopa; neural degeneration; neuromuscular disorder; neuromuscular disorder chemotherapy; pathologic process; patient oriented research; purinergic receptor; serotonin receptor; sleep disorders; transdermal drug delivery

Improving the translation of recent findings from basic laboratory research to better therapies for neurologic disease constitutes a major challenge for the neurosciences as well as a critical goal for Branch research. ETB recent contributions to the development of several treatments for Parkinson?s disease (PD) illustrate approaches to some of the relevant issues. Building on our previus findings in rodent and primate models of PD, our clinical study using a highly selective adenosine A2A antagonist (KW-6002) discovered the ability of A2A receptor blockade to benefit motor dysfunction. These results confirmed that drugs capable of blocking A2A receptors confer therapeutic benefit to parkinsonian patients and exemplify a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials. Other of our related investigator-initiated, proof-of-concept clinical studies also made important advances relevant to the treatment of PD, including our recently completed trials involving non-dopaminergic treatments that target selected striatal transmitter receptors, such as serotonin 5HT1A and alpha-2 adrenergic autoreceptors. Our two separate studies using sarizotan, a 5HT1A agonist, and fipamezole, an alpha2 adrenergic antagonist, suggested that 5HT1A receptor stimulation and alpha 2-adrenergic receptor blockade in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that drugs of these types may be useful as adjuvant in the treatment of this disorder. During the past year we also designed and started the implementation of other translational proof-of principle studies aimed at advancing the treatment of motor complications in PD. These trials evaluate the effects of serotonin 5HT2 A/C blockade, combined AMPA and NMDA receptor-blockade and continuous transdermal dopaminergic stimulation on parkinsonian symptoms and on motor complications in advanced PD, including motor fluctuations and levodopa-induced dyskinesias. In addition to these investigations on PD, our branch also conducted last year 2 research projects on the pathophysiology of the restless legs syndrome (RLS). In the first study, the role of dopaminergic mechanisms in spinal flexor reflex circuitry was investigated in a double blind randomized trial of ropinirole versus placebo in patients with RLS. The second study is evaluating the potential contribution of sensorimotor gating abnormalities in the pathophysiology of this condition. These studies are important to understand the possible mechanisms underlying this frequent neurological disorder.

将基础实验室研究的最新发现转化为更好的神经疾病治疗方法，是神经科学面临的一项重大挑战，也是分科研究的一个关键目标。ETB最近对几种帕金森治疗方法的发展有何贡献？帕金森病（PD）说明了一些相关问题的方法。基于我们之前在啮齿动物和灵长类动物PD模型中的发现，我们使用高选择性腺苷A2A拮抗剂（KW-6002）进行的临床研究发现，A2A受体阻断能够改善运动功能障碍。这些结果证实，能够阻断A2A受体的药物能够给帕金森患者带来治疗益处，并举例说明了一种成功地将PD治疗的新方法从不断发展的研究概念过渡到关键临床试验的策略。我们的其他相关研究人员发起的概念验证临床研究也在PD治疗方面取得了重要进展，包括我们最近完成的涉及非多巴胺能治疗的试验，该试验针对选定的纹状体递质受体，如血清素5HT1A和α -2肾上腺素能自受体。我们的两项独立研究使用了5HT1A激动剂沙唑坦和α 2肾上腺素能拮抗剂菲帕唑，表明左旋多巴治疗的帕金森患者5HT1A受体刺激和α 2肾上腺素能受体阻断可以调节纹状体多巴胺能功能，这些类型的药物可能是治疗这种疾病的辅助药物。在过去的一年中，我们还设计并开始实施了其他旨在推进PD运动并发症治疗的转化性原理验证研究。这些试验评估了5 -羟色胺5HT2 A/C阻断、AMPA和NMDA受体联合阻断以及持续经皮多巴胺能刺激对帕金森症状和晚期PD运动并发症（包括运动波动和左旋多巴诱导的运动障碍）的影响。