Pathogenesis And Treatment Of Neurodegenerative Disease

将基础实验室研究的最新发现转化为更好的神经系统疾病治疗方法是神经科学面临的主要挑战，也是分支研究的关键目标。ETB最近对帕金森病几种治疗方法的发展做出了贡献？的疾病（PD）说明了一些相关问题的方法。基于我们先前在啮齿动物和灵长类动物PD模型中的发现，我们的临床研究发现了各种药物的潜在治疗益处，包括我们最近完成的涉及靶向选定纹状体递质受体（如腺苷A2 a、5-羟色胺5 HT 1A和α-2肾上腺素能自身受体）的非多巴胺能治疗的试验。我们已经证明，这些类型的药物可以调节纹状体多巴胺能功能，并可能是有用的辅助治疗这种疾病。这些工作是成功地将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。 在过去的一年中，我们进行了额外的翻译证明的原则研究，旨在推进运动并发症的治疗PD。这些试验评价了5-羟色胺5 HT 2 A/C阻断和持续经皮多巴胺能刺激对帕金森病症状和晚期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。 除了这些对帕金森病的研究外，我们的分支还在去年完成了两个关于不宁腿综合征（RLS）病理生理学的研究项目。在第一项研究中，多巴胺能机制在脊髓屈肌反射回路中的作用在RLS患者中进行了罗匹尼罗与安慰剂的双盲随机试验。第二项研究评估了感觉运动门控异常在这种疾病的病理生理学中的潜在作用。这些研究对于了解这种常见神经系统疾病的可能机制非常重要。

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 previous findings in rodent and primate models of PD, our clinical studies have discovered the potential therapeutic benefit of various drugs, including our recently completed trials involving non-dopaminergic treatments that target selected striatal transmitter receptors, such as adenosine A2a, serotonin 5HT1A and alpha-2 adrenergic autoreceptors. We have demonstrated that drugs of these types can modulate striatal dopaminergic function and may be useful as adjuvant in the treatment of this disorder. These works exemplify a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials. During the past year we conducted additional translational proof-of principle studies aimed at advancing the treatment of motor complications in PD. These trials evaluated the effects of serotonin 5HT2 A/C 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 completed last year two 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 evaluated 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.