Nicotine and Neuroprotection in Parkinson's Disease

描述（申请人提供）：帕金森病（PD）是一种进行性神经退行性疾病。药物和手术治疗的结合改善了大多数PD患者的生活质量。但实质性黑质不断退化，基底节区多巴胺随之减少，最终导致严重的衰弱状态。努力减缓疾病，即使是很小的程度，也会延长患者的寿命，提高患者的生活质量，减轻国家对PD患者的护理成本负担。目前还没有药物可以减缓这种疾病的进展。在这项提议中，我们假设，在所有可用的化合物中，尼古丁显示出重要的希望，作为PD退行性多巴胺能神经元的神经保护剂。我们将讨论支持这一观点的证据：在几种神经毒性模型中，尼古丁具有神经保护作用。尼古丁的神经保护作用是通过几个已建立的细胞存活和抗凋亡分子级联介导的。PD中退行性多巴胺能神经元确实表现出凋亡性死亡的证据。在PD动物模型中，尼古丁具有神经保护作用。尼古丁的神经保护作用是通过大量存在于黑质和纹状体中的α 4 - β 2和aIpha7 - β 2尼古丁受体激活P13K/Akt抗凋亡通路来实现的。并提出了一项初步的研究计划，拟进行经皮尼古丁贴剂的临床试验。

DESCRIPTION (provided by applicant): 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 substantial 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 P13K/Akt antiapoptotic pathways by alpha4 - beta2 and aIpha7 - beta2 nicotinic receptors, which are abundant in the substantial nigra and striatum. A tentative research plan to conduct clinical trial using Transdermal nicotine patches is also proposed.