Nicotinic and neuroprotection in a parkinson mouse model

描述（由申请方提供）：我们的目标是了解黑质纹状体损伤和尼古丁治疗对基底神经节中烟碱受体（nAChR）亚型的影响，并确定任何变化与神经保护的关系。这项工作的基本原理部分是基于流行病学研究，研究表明吸烟者帕金森病（PD）的发病率降低。这种明显的神经保护作用可能是由于烟草中的尼古丁，因为尼古丁在各种实验模型中保护黑质纹状体损伤。尼古丁通过刺激nAChR发挥作用。我们假设尼古丁介导的保护对黑质纹状体损伤发生的nAChR亚型的变化的结果。我们的初步数据显示，MPTP治疗后，nAChRs亚型及其功能发生了差异性变化。在本提案中，我们将测试尼古丁调节nAChRs的作用，研究其对黑质纹状体变性的神经保护作用，并研究其作用机制。这将通过以下具体目标来实现。(1)我们将测试尼古丁给药影响MPTP治疗小鼠的nAChR表达和功能的假设。虽然众所周知尼古丁暴露会上调对照动物的nAChR，但仍需进行研究以确定其在黑质纹状体损伤后的影响。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检验尼古丁诱导的nAChR变化与针对黑质纹状体损伤的神经保护相关的假设。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尼古丁受体亚型，我们将研究尼古丁是否能保护nAChR敲除小鼠免受黑质纹状体损伤。(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。我们将调查的假设，营养因子，如碱性成纤维细胞生长因子（bFGF）和脑源性神经营养因子（BDNF），以及免疫介质，如白细胞介素-6，参与。这些研究将增强我们对慢性黑质纹状体损伤和尼古丁治疗后nAChR表达和功能变化的认识。这可能允许设计用于PD的神经保护策略，PD是一种目前仅可用对症治疗的疾病。

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.