Nicotine and Neuroprotection in Parkinson's Disease

尼古丁与帕金森病的神经保护

• 批准号: 7012726
• 负责人: JAYARAMAN RAO
• 金额: $ 2.84万
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012726
• 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）：帕金森氏病（PD）是进行性神经退行性疾病。医疗和手术治疗的结合改善了大多数PD患者的生活质量。但是，基底神经节中大量nigra的变性和随之而来的多巴胺丧失最终导致严重令人衰弱的状态。减慢疾病的努力甚至在很小的程度上会延长寿命并改善患者的生活质量，并减轻PD患者的全国护理费用负担。目前，没有药物可以减慢疾病的进展。在这一提案中，假设在所有可用化合物中，尼古丁在PD中表现出成为退化多巴胺能神经元的神经保护剂的明显希望。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个良好确定的细胞存活和抗凋亡分子级联腔的介导的，3。pd中的多巴胺神经元在PD中确实显示了apopticotic死亡的证据。尼古丁的神经保护作用是通过α4 -beta2和aipha7 -aipha7 -beta2烟碱受体激活p13k/akt抗凋亡途径来实现的，这些受体在实质的Nigra和纹状体中很丰富。还提出了一项暂定研究计划，以使用透皮尼古丁斑块进行临床试验。