Nicotine and Neuroprotection in Parkinson's Disease

尼古丁与帕金森病的神经保护

• 批准号: 6663182
• 负责人: JAYARAMAN RAO
• 金额: $ 10.42万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6663182
• 关键词: Parkinson's disease; chemoprevention; clinical research; cooperative study; human subject; human therapy evaluation; nervous system disorder chemotherapy; neuropharmacology; neuroprotectants; nicotine; patient oriented research

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.

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改善了大多数帕金森病患者的生活质量。但黑质不断退化，基底神经节多巴胺随之减少，最终导致严重的衰弱状态。即使是小程度地减缓疾病进展的努力，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。在该提案中，假设在所有可用的化合物中，尼古丁显示出作为帕金森病中退化的多巴胺能神经元的神经保护剂的重要前景。我们将讨论支持以下观点的证据：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成熟的细胞存活和抗凋亡分子级联介导的，3. PD 中退化的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 α4 - β2 和 α7 - β2 烟碱受体激活 P13K/Akt 抗凋亡途径来实现的，这些受体在黑质和纹状体中含量丰富。还提出了使用透皮尼古丁贴剂进行临床试验的初步研究计划。