Nicotinic receptors as molecular targets to reduce L-dopa-induced dyskinesias in

描述(申请人提供)：虽然L-多巴疗法是治疗帕金森氏症最有效的疗法之一，但其长期使用与发展L-多巴诱导的运动障碍或异常不自主运动(AIMS)有关，后者可能与帕金森氏症本身一样致残。目前治疗运动障碍的药物非常有限，主要由金刚烷胺组成，这是一种仅有一定疗效的药物。因此，治疗L-多巴诱发的运动障碍的新疗法至关重要。我们最近的工作表明，尼古丁治疗降低了L-多巴在大鼠、小鼠和猴子帕金森模型中诱导的AIMS。这些跨物种的数据表明，尼古丁可能对治疗L多巴诱导的运动障碍有好处。然而，尼古丁刺激体内的多个尼古丁受体(NAChRs)，导致预期的反应，但也会对心血管、胃肠和其他系统产生有害的副作用。重要的是，外周和中枢神经系统中的nAChR亚型是不同的。我们的总体目标是在nAChR亚型中确定分子靶点，以支持中枢神经系统选择性治疗L多巴诱导的运动障碍的开发。这些知识将导致在减少运动障碍方面具有最佳疗效的治疗方法，并将不良反应降至最低。为了实现这一目标，我们有两个具体目标；目标1的目标是目标识别/验证，目标2的目标是临床前原则验证。在目标1中，我们将使用nAChR缺失突变小鼠来阐明与L多巴诱导的运动障碍的发生有关的nAChR亚型。对(-/-)小鼠的研究提供了一个优势，即它们允许直接识别对L多巴诱导的AIMS的发展至关重要的nAChR群体(S)。我们将使用22、14和16(-/-)小鼠，因为包含这些亚单位的nAChRs存在于整个中枢神经系统和黑质纹状体系统中。这些研究将与科罗拉多大学的莎伦·格雷迪博士合作完成，格雷迪博士目前正在培育这样的小鼠和它们的野生型同行。本工作的结果将为选择nAChR激动剂以对抗L多巴诱导的AIMS的发展提供合理的依据。这些实验构成了AIM 2的基础，AIM 2评估了相关亚型选择性nAChR激动剂降低L多巴诱导的AIMS的能力。帕金森症也将接受测试，以确保具有抗运动障碍特性的药物不会恶化运动功能。拟议的研究将确定新的nAChR靶点，用于治疗干预，以减少L-多巴诱导的帕金森病运动障碍。这项工作具有很高的翻译性，因为它形成了开发具有最大潜力减少运动障碍的nAChR定向配体的关键第一步。后续的步骤超出了这项提案的范围，将在临床前研究中测试这些药物，并最终在临床环境中测试它们在治疗L-多巴诱导的帕金森氏症运动障碍方面的有效性。 公共卫生相关性：我们的数据显示，在几种不同的帕金森病动物模型中，尼古丁管理减少了L-多巴诱导的运动障碍，包括猴子、大鼠和小鼠。我们的目标是使用两种方法，烟碱受体缺失突变小鼠和烟碱受体亚型选择性激动剂，鉴定介导尼古丁抗运动障碍作用的烟碱受体亚型。这些研究有可能为使用针对尼古丁胆碱能系统的药物治疗帕金森病的运动障碍开辟新的研究方向。

DESCRIPTION (provided by applicant): Although L-dopa treatment is one of the most effective therapies for Parkinson's disease, its long-term use is associated with the development L-dopa-induced dyskinesias or abnormal involuntary movements (AIMs) that can be as disabling as Parkinson's disease itself. Current drug treatments for dyskinesias are very limited and consist primarily of amantadine a drug that is only modestly effective. New therapies for the treatment of L- dopa-induced dyskinesias are therefore critical. Our recent work shows that nicotine treatment reduces L- dopa-induced AIMs in rat, mouse and monkey parkinsonian models. These data across species suggest that nicotine may be of benefit for the treatment of L-dopa-induced dyskinesias. However, nicotine stimulates multiple nicotinic receptors (nAChRs) in the body resulting in the desired response but also unwanted side effects on the cardiovascular, gastrointestinal and other systems. Importantly, the nAChR subtypes in the peripheral and central nervous system are different from one another. Our overall goal is to identify molecular targets among nAChR subtypes to support development of CNS selective therapies for L-dopa-induced dyskinesias. Such knowledge would lead to treatments with optimal efficacy in reducing dyskinesias and a minimum of adverse effects. To approach this, we have two specific aims; the objective of Aim 1 is target identification/validation and that of Aim 2 is pre-clinical proof-of-principle. In Aim 1, we will use nAChR null mutant mice to elucidate the nAChR subtypes involved in the generation of L-dopa-induced dyskinesias. Studies with (-/-) mice offer the advantage that they allows for direct identification of the nAChR population(s) important for the development of L-dopa-induced AIMs. We will use 22, 14, and 16 (-/-) mice since nAChRs containing these subunits are present throughout the CNS and in the nigrostriatal system. These studies will be done in collaboration with Dr. Sharon Grady at the University of Colorado, who currently breeds such mice and their wildtype counterparts. The results of this work will provide a rational basis for the selection of nAChR agonists to test against the development of L-dopa-induced AIMs. Such experiments form the basis of Aim 2, which evaluates the ability of the relevant subtype selective nAChR agonists to reduce L-dopa-induced AIMs. Parkinsonism will also be tested to ensure that drugs with antidyskinetic properties do not worsen motor function. The proposed studies will identify novel nAChR targets for therapeutic intervention to reduce L-dopa- induced dyskinesias in Parkinson's disease. This work is highly translational as it forms a crucial first step for developing nAChR-directed ligands with the greatest potential for reducing dyskinesias. Subsequent steps, which are beyond the scope of this proposal, will be to test these drugs in pre-clinical studies, and eventually in a clinical setting, for their effectiveness in the treatment of L-dopa-induced dyskinesias for Parkinson's disease. PUBLIC HEALTH RELEVANCE: Our data show that nicotine administration reduces L-dopa-induced dyskinesias in several different parkinsonian animal models, including monkeys, rats and mice. Our objective is to identify the nicotinic receptor subtypes that mediate nicotine's antidyskinetic effect using two approaches, nicotinic receptor null mutant mice and nicotinic receptor subtype selective agonists. These studies have the potential to open up a new research direction for the treatment of dyskinesias in Parkinson's disease using drugs targeted to the nicotinic cholinergic system.