Nicotine and Neuroprotection in Parkinson's Disease

描述（由申请人提供）：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提高了大多数PD患者的生活质量。但是，黑质退化的无情进展和随之而来的基底神经节多巴胺的丧失最终导致严重的衰弱状态。即使在很小程度上减缓疾病的努力也会延长患者的寿命，提高患者的生活质量，减轻国家对PD患者的护理费用负担。目前还没有药物可以减缓疾病的进展。在该建议中，假设在所有可用的化合物中，尼古丁显示出作为PD中变性多巴胺能神经元的神经保护剂的显著前景。我们将讨论证据来支持这一点：1。尼古丁在几种神经毒性模型中具有神经保护作用。尼古丁的神经保护作用是通过几个良好建立的细胞存活和抗凋亡分子级联介导的。PD中变性的多巴胺能神经元确实显示出凋亡性死亡的证据。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α 4-β 2和α 7-β 2烟碱受体激活P13 K/Akt抗凋亡途径来实现的，所述烟碱受体在黑质和纹状体中丰富。并提出了使用尼古丁贴剂进行临床试验的初步研究计划。

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.