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不自主运动异常（AIMs）的发展有关，这可能与帕金森病本身一样致残。目前对运动障碍的药物治疗非常有限，主要由金刚烷胺组成，这种药物只有适度的效果。因此，治疗左旋多巴诱导的运动障碍的新疗法至关重要。我们最近的研究表明，尼古丁治疗可以降低大鼠、小鼠和猴子帕金森模型中左旋多巴诱导的AIMs。这些跨物种的数据表明，尼古丁可能对左旋多巴引起的运动障碍的治疗有益。然而，尼古丁会刺激体内的多种尼古丁受体（nachr），从而产生预期的反应，但也会对心血管、胃肠道和其他系统产生意想不到的副作用。重要的是，外周神经系统和中枢神经系统的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，以支持开发用于左旋多巴诱导的运动障碍的中枢神经系统选择性疗法。这些知识将导致治疗在减少运动障碍和最小的不良反应的最佳疗效。为此，我们有两个具体目标；Aim 1的目标是目标识别/验证，Aim 2的目标是临床前原理证明。在Aim 1中，我们将使用nAChR零突变小鼠来阐明参与左旋多巴诱导的运动障碍产生的nAChR亚型。对（-/-）小鼠的研究提供了一个优势，即它们允许直接鉴定对左旋多巴诱导的AIMs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（University of Colorado）的莎伦·格雷迪（Sharon Grady）博士合作完成，她目前正在培育这种小鼠和它们的野生型同类。本研究结果将为选择nAChR激动剂进行左旋多巴诱导的AIMs抗发展试验提供合理依据。这些实验构成了Aim 2的基础，目的是评估相关亚型选择性nAChR激动剂降低左旋多巴诱导的AIMs的能力。帕金森氏症也将进行测试，以确保具有抗运动障碍特性的药物不会使运动功能恶化。拟议的研究将确定新的nAChR靶点，用于治疗干预，以减少左旋多巴诱导的帕金森病运动障碍。这项工作是高度翻译的，因为它形成了开发nachr导向配体的关键的第一步，具有最大的减少运动障碍的潜力。接下来的步骤是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引起的帕金森病运动障碍方面的有效性，这超出了本提案的范围。

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.