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

描述（由申请人提供）：虽然左旋多巴治疗是帕金森病最有效的治疗方法之一，但其长期使用与左旋多巴诱导的运动障碍或异常不自主运动（AIM）的发展相关，这些运动障碍或异常不自主运动（AIM）可能与帕金森病本身一样致残。目前治疗运动障碍的药物非常有限，主要包括金刚烷胺，一种只有适度有效的药物。因此，治疗左旋多巴诱导的运动障碍的新疗法至关重要。我们最近的工作表明，尼古丁治疗可减少大鼠、小鼠和猴帕金森病模型中L-多巴诱导的AIM。这些跨物种的数据表明，尼古丁可能有利于治疗左旋多巴诱导的运动障碍。然而，尼古丁刺激体内的多种烟碱受体（nAChR），导致期望的反应，但也对心血管、胃肠道和其他系统产生不希望的副作用。重要的是，外周和中枢神经系统中的nAChR亚型彼此不同。我们的总体目标是确定nAChR亚型中的分子靶点，以支持开发针对左旋多巴诱导的运动障碍的CNS选择性疗法。这样的知识将导致治疗具有最佳疗效，减少运动障碍和最小的不良反应。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的目标是临床前原理验证。在目标1中，我们将使用nAChR无效突变小鼠来阐明参与L-多巴诱导的运动障碍的产生的nAChR亚型。使用（-/-）小鼠的研究提供了这样的优势，即它们允许直接鉴定对L-多巴诱导的AIM的发展重要的nAChR群体。我们将使用22、14和16（-/-）只小鼠，因为含有这些亚基的nAChR存在于整个CNS和黑质纹状体系统中。这些研究将与科罗拉多大学的Sharon Grady博士合作完成，他目前正在饲养这种小鼠及其野生型小鼠。这项工作的结果将提供一个合理的基础上选择nAChR激动剂，以测试对L-多巴诱导的AIM的发展。这些实验形成了目标2的基础，目标2评价了相关亚型选择性nAChR激动剂减少左旋多巴诱导的AIM的能力。帕金森症也将进行测试，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治疗干预的目标，以减少帕金森病中左旋多巴诱导的运动障碍。这项工作是高度翻译的，因为它形成了开发具有减少运动障碍的最大潜力的nAChR定向配体的关键的第一步。随后的步骤超出了本提案的范围，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左旋多巴诱导的帕金森病运动障碍中的有效性。 公共卫生相关性：我们的数据表明，尼古丁管理减少左旋多巴诱导的运动障碍，在几个不同的帕金森病动物模型，包括猴子，大鼠和小鼠。我们的目标是确定烟碱受体亚型介导尼古丁的抗运动障碍的作用，使用两种方法，烟碱受体无效突变小鼠和烟碱受体亚型选择性激动剂。这些研究有可能为使用靶向烟碱胆碱能系统的药物治疗帕金森病中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.