Statin and Phenylacetate in MPTP Mouse Model

MPTP 小鼠模型中的他汀类药物和苯乙酸

• 批准号: 7033113
• 负责人: KALIPADA PAHAN
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033113
• 关键词: 3,4 dihydroxyphenylacetate; Parkinson' s disease; antiinflammatory agents; apoptosis; brain derived neurotrophic factor; brain disorder chemotherapy; brain metabolism; combination chemotherapy; cytokine; disease /disorder model; dopamine; homovanillate; laboratory mouse; lovastatin; methylphenyltetrahydropyridine; neural degeneration; neuroprotectants; nitric oxide synthase; nonhuman therapy evaluation; phenylacetates; polymerase chain reaction; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is one of the most devastating neurodegenerative disorders in humans. Despite intense investigations, no effective therapy is available. Although its etiology remains unknown, it is believed that complex interaction between environmental and genetic factors leads to activation of glia and induction of broad-spectrum inflammatory reactions followed by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Consistently, enhanced expression of inducible nitric oxide synthase (iNOS) and pro inflammatory cytokines (IL-1a, IL-6 and TNF-a) has been found in association with glial cells in the SNpc of patients with PD. We have found that lovastatin, a drug approved for hypercholesterolemia, and sodium phenylacetate (NaPA), a drug approved for urea cycle disorders in children, inhibit the expression of iNOS and pro inflammatory cytokines in glial cells by inhibiting Ras - NF-kB. Our recent studies have shown that drinking water containing NaPA markedly inhibits the disease process of experimental allergic encephalomyelitis (EAE), an animal model of Multiple Sclerosis (MS), as well as the expression of proinflammatory molecules in the CNS of EAE mice. Similarly sodium phenylbutyrate (NaPB), a synthetic precursor of NaPA and a FDA-approved drug, also inhibited the inflammatory disease process of EAE. Consistently, it has been also shown that lovastatin inhibits the disease process of EAE in different animal models. These results raise the possibility that lovastatin, NaPA and NaPB may turn out to be antineuroinflammatory drugs. Unlike MS, PD is not an autoimmune disorder. However, similar to MS, inflammation within the CNS plays a major role in the loss of dopaminergic neurons in SNpc of PD patients. Therefore, it is of worth trying if oral administration of lovastatin, NaPA and NaPB attenuates the expression of proinflammatory molecules (iNOS and cytokines) and the loss of dopaminergic neurons in an animal model of PD. A positive outcome of this grant proposal will further attest the anti neuroinflammatory role of lovastatin, NaPA and NaPB, and enhance the possibility of treating PD patients with these FDA approved drugs as primary or adjunct therapy.

描述（由申请人提供）： 帕金森病（PD）是人类最具破坏性的神经退行性疾病之一。尽管进行了大量研究，但仍没有有效的治疗方法。尽管其病因尚不清楚，但据信环境和遗传因素之间复杂的相互作用导致神经胶质细胞活化并诱导广谱炎症反应，随后导致黑质致密部（SNpc）中的多巴胺能神经元变性。一致地，已发现诱导型一氧化氮合酶 (iNOS) 和促炎细胞因子（IL-1a、IL-6 和 TNF-a）表达增强与 PD 患者 SNpc 中的神经胶质细胞相关。我们发现洛伐他汀（一种被批准用于治疗高胆固醇血症的药物）和苯乙酸钠（NaPA）（一种被批准用于治疗儿童尿素循环障碍的药物）通过抑制Ras - NF-kB来抑制神经胶质细胞中iNOS和促炎细胞因子的表达。我们最近的研究表明，含有NaPA的饮用水可以显着抑制实验性过敏性脑脊髓炎（EAE）（一种多发性硬化症（MS）动物模型）的疾病进程，以及EAE小鼠中枢神经系统中促炎分子的表达。同样，苯丁酸钠（NaPB）是 NaPA 的合成前体，也是 FDA 批准的药物，也能抑制 EAE 的炎症过程。一致地，洛伐他汀在不同动物模型中也显示出抑制 EAE 的疾病过程。这些结果提出了洛伐他汀、NaPA 和 NaPB 可能成为抗神经炎症药物的可能性。与 MS 不同，PD 不是一种自身免疫性疾病。然而，与多发性硬化症类似，中枢神经系统内的炎症在帕金森病患者的 SNpc 中多巴胺能神经元的丧失中起着重要作用。因此，如果口服洛伐他汀、NaPA 和 NaPB 能够减弱 PD 动物模型中促炎分子（iNOS 和细胞因子）的表达和多巴胺能神经元的丧失，那么值得尝试。该拨款提案的积极成果将进一步证明洛伐他汀、NaPA 和 NaPB 的抗神经炎症作用，并提高使用 FDA 批准的这些药物作为主要或辅助疗法治疗 PD 患者的可能性。