Nicotine and Neuroprotection in Parkinson's Disease

帕金森病（Parkinson's disease，PD）是一种进行性神经退行性疾病。结合医疗和 手术治疗改善了大多数PD患者的生活质量。但无情的进步 黑质的退化和随之而来的基底神经节多巴胺的丢失， 会导致严重的虚弱状态努力减缓疾病，即使是在很小的程度上， 延长和改善患者的生活质量，并减轻PD患者护理费用的国家负担。 目前还没有药物可以减缓这种疾病的发展。在本提案中， 假设，在所有可用的化合物中，尼古丁显示出显著的前景， 神经保护剂，用于PD中变性的多巴胺能神经元。我们将讨论证据， 支持： 1.尼古丁在几种神经毒性模型中具有神经保护作用， 2.尼古丁的神经保护作用是通过几种公认的细胞存活和 抗凋亡分子级联， 3. PD中的变性多巴胺能神经元确实显示出凋亡性死亡的证据， 4.尼古丁在PD动物模型中具有神经保护作用， 5.尼古丁的神经保护作用是通过激活PI 3 K/Akt抗凋亡蛋白来实现的。 通过α 4-β 2和α？- β 2烟碱受体，在人体内大量存在 黑质和纹状体。 并提出了使用尼古丁贴剂进行临床试验的初步研究计划。

Parkinson's disease (PD) is progressive neurodegenerative disorder. A combination of medical and surgical treatments has improved the quality of the lives of most PD patients. But the relentless progression of degeneration of the substantia nigra and consequent loss of dopamine in the basal ganglia ultimately leads to a severe debilitating state. Efforts to slow the disease even to a small degree will extend the life span and improve the quality of a patient's life and reduce the national burden of cost of care of PD patients. At present there are no drugs that can slow the progression of the disease. In this proposal it is hypothesized, that among all the available compounds, nicotine shows significant promise to be a neuroprotective agent for the degenerating dopaminergic neurons in PD. We will discuss evidence to support that: 1. Nicotine is neuroprotective in several models of neurotoxicity, 2. The neuroprotective effects of nicotine are mediated via several well established cell survival and anti-apoptotic molecular cascades, 3. The degenerating dopaminergic neurons in PD do show evidence of apoptotic death, 4. Nicotine is neuroprotective in animal models of PD, and 5. Nicotine's neuroprotective actions are accomplished by the activation of PI3K/Akt antiapoptotic pathways byalpha4 - beta2 andalpha? - beta2 nicotinic receptors, which areabundant inthesubstantia nigra and striatum. A tentative research plan to conduct clinical trial using Transdermal nicotine patches is also proposed.