Nicotinic and neuroprotection in a parkinson mouse model

帕金森小鼠模型中的烟碱和神经保护

• 批准号: 6844758
• 负责人: MARYKA QUIK
• 金额: $ 29.97万
• 依托单位: PARKINSON'S INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844758
• 关键词: Parkinson' s disease; brain derived neurotrophic factor; chemoprevention; cholinergic agents; corpus striatum; disease /disorder model; dopamine; fibroblast growth factor; genetically modified animals; interleukin 6; laboratory mouse; methylphenyltetrahydropyridine; neuropharmacology; neuroprotectants; nicotine; nicotinic receptors; protein structure; protein structure function; receptor expression; substantia nigra

DESCRIPTION (provided by applicant): Our goal is to understand the effects of nigrostriatal damage and nicotine treatment on nicotinic receptor (nAChR) subtypes in the basal ganglia, and determine the relationship of any changes to neuroprotection. The rationale for such work is based, in part, on epidemiological studies showing that there is a decreased incidence of Parkinson's disease (PD) in smokers. This apparent neuroprotection may be due to nicotine in tobacco since nicotine protects against nigrostriatal damage in various experimental models. Nicotine exerts its effects by stimulating nAChRs. We hypothesize that nicotine-mediated protection against nigrostriatal damage occurs as a consequence of changes in nAChR subtypes. Our preliminary data show that there are differential changes in nAChRs subtypes and their function after MPTP treatment. In this proposal, we will test the effects of nicotine to modulate nAChRs, study its neuroprotective effects against nigrostriatal degeneration and investigate its mechanism(s) of action. This will be approached through the following Specific Aims. (1) We will test the hypothesis that nicotine administration influences nAChR expression and function in MPTP-treated mice. Although nicotine exposure is well-known to upregulate nAChRs in control animals, studies to determine its effects after nigrostriatal damage remain to be done. Next (2) we will test the hypothesis that nicotine-induced changes in nAChRs correlate with neuroprotection against nigrostriatal damage by measuring various markers of striatal dopaminergic function. These data will be correlated to changes in nAChRs to determine whether receptor alterations are linked to neuroprotection. (3) To determine whether specific nicotinic receptor subtypes are involved we will we will study whether nicotine protects against nigrostriatal damage in nAChR knockout mice. (4) Finally, experiments will be done to study the molecular mechanisms that mediate nicotine-induced neuroprotection. We will investigate the hypothesis that trophic factors such as basic fibroblast growth factor (bFGF) and brain derived neurotrophic factor (BDNF), as well as immune mediators such as interleukin-6, are involved. These studies will enhance our knowledge of the changes in nAChR expression and function with chronic nigrostriatal damage and nicotine treatment. This may allow for the design of neuroprotective strategies for PD, a disorder for which only symptomatic treatment is currently available.

描述（由申请人提供）：我们的目标是了解基底神经节中斑纹纹状体损伤和尼古丁治疗对烟碱受体（NACHR）亚型的影响，并确定任何变化与神经保护的关系。此类工作的理由部分基于流行病学研究表明，吸烟者中帕金森氏病（PD）的发生率降低。这种明显的神经保护可能是由于烟草中的尼古丁造成的，因为尼古丁在各种实验模型中都可以防止黑质纹状体损害。尼古丁通过刺激NACHRS发挥其作用。我们假设尼古丁介导的针对黑质纹状体损害的保护是由于NACHR亚型的变化而发生的。我们的初步数据表明，NACHRS亚型及其在MPTP治疗后的功能发生变化。在此提案中，我们将测试尼古丁调节NACHR的作用，研究其针对黑杂交变性的神经保护作用，并研究其作用机制。这将通过以下特定目的来实现。 （1）我们将检验以下假设：尼古丁给药会影响MPTP处理的小鼠的NACHR表达和功能。尽管尼古丁的暴露是在对照动物中上调NACHR的众所周知的，但是在骨纹状体损害后确定其作用的研究仍有待完成。接下来（2）我们将通过测量纹状体多巴胺能功能的各种标志物来测试尼古丁诱导的NACHRS变化与针对黑质纹状体损伤的神经保护作用相关的假设。这些数据将与NACHR的变化相关，以确定受体改变是否与神经保护有关。 （3）为了确定是否涉及特定的烟碱受体亚型，我们将研究尼古丁是否可以防止NACHR敲除小鼠中的黑质层损伤。 （4）最后，将进行实验以研究介导尼古丁诱导的神经保护的分子机制。我们将研究以下假设：诸如基本成纤维细胞生长因子（BFGF）和脑衍生的神经营养因子（BDNF）以及诸如Interleuukin-6之类的免疫介质等营养因子涉及。这些研究将增强我们对NACHR表达和功能变化的了解，并通过慢性纹状体损伤和尼古丁治疗。这可能允许设计PD的神经保护策略，该疾病目前只有症状治疗。