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

烟碱受体作为减少左旋多巴引起的运动障碍的分子靶点

基本信息

批准号：
8040978
负责人：
MARYKA QUIK
金额：
$ 22.25万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8040978
关键词：
Adverse effects Agonist Amantadine Animal Model Behavioral Brain Breeding Cardiovascular system Clinical Collaborations Colorado Complex Data Deep Brain Stimulation Development Drosophila acetylcholine receptor alpha-subunit Drug Delivery Systems Dyskinetic syndrome Effectiveness Ensure Exhibits Generations Goals Knockout Mice Knowledge Lead Lesion Levodopa Ligands Mediating Modeling Molecular Target Monkeys Motor Mus Mutant Strains Mice Neuraxis Neurons Nicotine Nicotinic Receptors Operative Surgical Procedures Oxidopamine Parkinson Disease Parkinsonian Disorders Peripheral Pharmaceutical Preparations Population Property Rattus Research Rest System Testing Therapeutic Intervention Universities Validation Work abnormal involuntary movement base cholinergic drug efficacy drug testing effective therapy gastrointestinal mutant nigrostriatal system nonhuman primate novel pre-clinical preclinical study public health relevance receptor research study response

项目摘要

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.

描述（由申请人提供）：尽管L-DOPA治疗是帕金森氏病的最有效疗法之一，但其长期使用与发育L-DOPA诱导的运动障碍或异常非自愿运动（AIMS）有关，可以像帕金森氏病本身一样残疾。当前的运动障碍药物治疗非常有限，主要由一种仅适度有效的药物组成。因此，用于治疗L-多巴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，尼古丁的治疗可降低L-多巴多巴诱导的目标，而老鼠和猴子帕金森氏菌模型。跨物种的这些数据表明，尼古丁可能有益于治疗L-DOPA诱导的运动障碍。然而，尼古丁刺激体内的多种烟碱受体（NACHR），导致所需的反应，但对心血管，胃肠道和其他系统的副作用也有害。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亚型之间的分子靶标，以支持CNS选择性疗法的L-DOPA诱导的运动障碍。这种知识将导致在减少运动障碍和最小不良影响方面具有最佳疗效的治疗方法。为了解决这个问题，我们有两个具体的目标。 AIM 1的目的是目标识别/验证，而AIM 2的目标是临床前原则证明。在AIM 1中，我们将使用NACHR空突变小鼠阐明与L-DOPA诱导的运动障碍产生有关的NACHR亚型。对（ - / - ）小鼠的研究提供了一种优势，即他们允许直接识别NACHR种群，这对于开发L-DOPA诱导的目标很重要。我们将使用22、14和16只（ - / - ）小鼠，因为含有这些亚基的NACHR在整个中枢神经系统和黑质系统中存在。这些研究将与科罗拉多大学的沙龙·格雷迪博士合作完成，科罗拉多大学目前培养了小鼠及其野生型。这项工作的结果将为选择NACHR激动剂的选择提供合理的基础，以测试反对L-DOPA诱导的目标的发展。这种实验构成了目标2的基础，该基础评估了相关亚型选择性NACHR激动剂减少L-DOPA诱导的目标的能力。还将对帕金森氏症进行测试，以确保具有抗体性特性的药物不会恶化运动功能。拟议的研究将确定用于治疗干预的新型NACHR靶标，以减少帕金森氏病中L- dopa引起的运动障碍。这项工作是高度转化的，因为它构成了开发具有最大潜力减少运动障碍潜力的NACHR指导的配体的关键第一步。随后的步骤超出了该提案的范围，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-DOPA诱导的帕金森氏病的有效性。公共卫生相关性：我们的数据表明，尼古丁管理会在几种不同的帕金森氏症动物模型中减少L-DOPA引起的运动障碍，包括猴子，大鼠和小鼠。我们的目标是鉴定使用两种方法，即烟碱受体无效突变小鼠和烟碱受体亚型选择性激动剂，从而鉴定尼古丁受体亚型，这些烟碱受体亚型介导了尼古丁的抗体运动效应。这些研究有可能使用针对烟素胆碱能系统的药物为帕金森氏病治疗帕金森氏病的新研究方向。