Protective actions of the anti-inflammatory drug candidate 10-nitro-oleic acid in Parkinson’s disease

项目摘要 帕金森病（PD）的有效治疗是一种未满足的需求，因为目前的治疗方法 已证明对减缓或逆转疾病的进展无效。的确切 PD中选择性黑质纹状体细胞丢失的机制仍然知之甚少，但 越来越多的人认为氧化应激和神经炎症起着关键作用。在这 在这方面，新的药理学策略，基于Nrf 2依赖性抗氧化剂的激活， 组织修复反应，抑制促炎性NF-κ B依赖性细胞因子和 粘附分子表达和NADPH氧化酶-2（NOX-2）活性， 导致PD治疗。新的候选药物10-硝基油酸（10-NO2-OA）显示组织- 在多个临床前模型中的保护和抗炎作用，已清除5个1期 在107名受试者中进行了人体试验，目前正在进行与治疗慢性 肺部和肾脏疾病。值得注意的是，我们刚刚发现，10-NO2-OA很容易交叉 血脑屏障从这一观点出发，现在假设10-NO2-OA进入了 黑质纹状体区的大脑，并将抑制氧化应激和神经退行性疾病的PD 通过调节Nrf 2和NF-kB依赖的基因表达和抑制前 炎性NADPH氧化酶-2（Nox-2）活性。然后，我们建议研究临床前模型 确定10-NO2-OA在限制PD发病机制方面的疗效。这样做的理由 该项目是，建立治疗10-NO2-OA浓度在大脑中将 促进有益的多效性组织保护反应，因此代表了一种安全和 有效的药物策略，以防止多因素疾病如PD的进展。的 本提案的目标是：1）通过以下途径确定10-NO2-OA的神经保护潜力： 调节Nrf 2和NF-kB依赖的基因表达和抑制Nox-2活性， 2）评估10-NO2-OA在中脑中的PK及其神经保护作用 在大鼠PD鱼藤酮模型中的作用。成功完成拟议的研究计划 可以通过揭示一种新的药理学策略来减轻 PD的经济和临床负担。 .

PROJECT SUMMARY An effective cure for Parkinson's disease (PD) is an unmet need, since current treatments have proved ineffective to slow down or reverse the progression of the disease. The exact mechanisms of the selective nigrostriatal cell loss in PD are still poorly understood, but there is an increasing consensus that oxidative stress and neuro-inflammation play a critical role. In this regard, new pharmacological strategies, based on the activation of Nrf2-dependent antioxidant, tissue-repair responses, the inhibition of pro-inflammatory NF-kB-dependent cytokine and adhesion molecule expression, and NADPH oxidase-2 (NOX-2) activity, have shown promising results in PD therapy. The new drug candidate 10-nitro-oleic acid (10-NO2-OA) displays tissue- protective and anti-inflammatory actions in multiple preclinical models, has cleared 5 Phase 1 human trials in 107 subjects, and is now in Phase II studies related to the treatment of chronic pulmonary and renal diseases. Notably, we have just discovered that 10-NO2-OA readily cross the blood-brain barrier. From this insight, it is now hypothesized that 10-NO2-OA accesses the nigrostriatal region of the brain and will inhibit oxidative stress and neurodegeneration in PD through modulation of Nrf2- and NF-kB-dependent gene expression and inhibition of pro- inflammatory NADPH oxidase-2 (Nox-2) activity. Then, we propose to study preclinical models to define the efficacy of 10-NO2-OA in limiting the pathogenesis of PD. The rationale for this project is that the establishment of therapeutic 10-NO2-OA concentrations in the brain will promote beneficial pleiotropic tissue-protective responses, thus representing a safe and effective drug strategy to prevent the progression of a multi-factorial disease such as PD. The goals of this proposal are: 1) Define the neuroprotective potential of 10-NO2-OA through the modulation of Nrf2- and NF-kB-dependent gene expression and inhibition of Nox-2 activity in an in vitro model of PD, 2) Evaluate the PK of 10-NO2-OA in the midbrain and its neuroprotective effects in a rotenone model of PD in rat. Successful completion of the proposed research plan can have a significant positive impact by revealing a new pharmacological strategy to alleviate the economic and clinical burden of PD. .