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。内科和外科相结合的治疗改善了大多数帕金森病患者的生活质量。但黑质的持续退化和基底节中多巴胺的丧失最终导致严重的衰弱状态。即使只是很小程度的减缓疾病的努力，也将延长患者的寿命，提高患者的生活质量，并减轻国家对帕金森病患者的护理费用负担。目前还没有药物可以减缓疾病的进展。在这项提议中，它被假设，在所有可用的化合物中，尼古丁显示出显著的希望成为帕金森病患者退化的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：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反应来实现的；3.帕金森病模型中退化的多巴胺能神经元确实显示出凋亡死亡的证据；4.尼古丁在帕金森病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P13K/Akt抗凋亡通路来实现的，这两种受体丰富地存在于黑质和纹状体中。还提出了使用尼古丁贴片进行临床试验的试探性研究计划。

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.