Nicotinic and neuroprotection in a parkinson mouse model

描述(申请人提供)：我们的目标是了解黑质纹状体损伤和尼古丁治疗对基底节尼古丁受体(NAChR)亚型的影响，并确定任何变化与神经保护的关系。这项工作的理论基础部分是基于流行病学研究表明，吸烟者帕金森氏病(PD)的发病率有所下降。这种明显的神经保护可能是由于烟草中的尼古丁，因为在各种实验模型中，尼古丁可以保护黑质纹状体免受损害。尼古丁通过刺激nAChRs发挥作用。我们假设尼古丁介导的对黑质纹状体损伤的保护是由于nAChR亚型的变化而发生的。我们的初步数据显示，MPTP治疗后，nAChRs亚型及其功能有不同程度的变化。在这项研究中，我们将测试尼古丁对nAChRs的调节作用，研究其对黑质纹状体变性的神经保护作用，并探讨其作用机制(S)。这将通过以下具体目标来实现。(1)我们将验证尼古丁给药影响MPTP处理的小鼠nAChR表达和功能的假设。尽管众所周知，尼古丁暴露会上调对照组动物的nAChRs，但确定其在黑质纹状体损伤后的影响的研究仍有待完成。下一步(2)我们将通过测量纹状体多巴胺能功能的各种标记物来检验这一假设，即尼古丁诱导的nAChRs的变化与黑质纹状体损伤的神经保护相关。这些数据将与nAChRs的变化相关联，以确定受体变化是否与神经保护有关。(3)我们将研究尼古丁是否对nAChR基因敲除小鼠的黑质纹状体损伤有保护作用，以确定是否涉及特定的尼古丁受体亚型。(4)对尼古丁诱导的神经保护的分子机制进行实验研究。我们将探讨营养因子，如碱性成纤维细胞生长因子和脑源性神经营养因子，以及免疫介质，如白介素6，参与其中的假设。这些研究将加深我们对慢性黑质纹状体损伤和尼古丁治疗时nAChR表达和功能变化的了解。这可能允许为帕金森病设计神经保护策略，目前只有对症治疗才能治疗帕金森病。

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.