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

候选抗炎药物 10-硝基油酸对帕金森病的保护作用

基本信息

批准号：
9805542
负责人：
Roberto Di Maio
金额：
$ 43.04万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-17 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9805542
关键词：
Adriamycin PFS Affect Animal Disease Models Anti-inflammatory Antioxidants Area Blood - brain barrier anatomy Brain Brain region Cell Adhesion Molecules Cells Chronic Clinical Clinical Trials Complex Consensus Cutaneous Diabetes Mellitus Disease Disease Progression Dose Drug Kinetics Economics Epoxide hydrolase Event Gene Expression Goals Health Care Costs Heat shock proteins Human Hyperactive behavior In Vitro Incidence Inflammation Inflammatory Inflammatory Response Isomerism Kidney Diseases Lung diseases Mediating Mediator of activation protein Metabolism Midbrain structure Modeling Movement Disorders Myocardial Ischemia NADPH Oxidase NF-kappa B Nerve Degeneration Oleic Acids Oral Outcome Oxidative Stress PPAR gamma Parkinson Disease Parkinsonian Disorders Pathogenesis Pathogenicity Pharmaceutical Preparations Pharmacology Phase Play Pre-Clinical Model Protein Inhibition Pulmonary Hypertension Radioactivity Radiolabeled Rattus Reperfusion Therapy Research Role Rotenone Sepsis Signal Transduction Testing Therapeutic Tissues Toxicity Tests XDH gene age related base cytokine disease diagnosis drug candidate effective therapy efficacy testing in vitro Model insight kidney dysfunction mitochondrial dysfunction motor symptom neuroinflammation non-motor symptom novel novel drug class novel therapeutic intervention novel therapeutics phase 2 study preclinical study prevent protein aggregation protein misfolding renal ischemia response tissue repair

项目摘要

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. .

项目摘要帕金森氏病（PD）的有效治愈是一种未满足的需求，因为目前的治疗方法事实证明，减速或扭转疾病进展无效。确切的 PD中选择性黑质细胞损失的机制仍然很少了解，但是有越来越多的共识是，氧化应激和神经炎症起着至关重要的作用。在这个考虑到基于NRF2依赖性抗氧化剂的激活的新药理策略，组织修复反应，促炎性NF-KB依赖性细胞因子的抑制和粘附分子表达和NADPH氧化酶-2（NOX-2）活性已显示出有希望的结果PD治疗。新药候选10-硝基酸（10-NO2-OA）显示组织 - 多种临床前模型中的保护性和抗炎作用已清除5阶段1 在107名受试者中的人体试验，现在正在与慢性治疗有关的II期研究中肺部和肾脏疾病。值得注意的是，我们刚刚发现10-no2-oa很容易交叉血脑屏障。从这个见解，现在可以假设10-No2-OA访问脑纹状体区域，将抑制PD的氧化应激和神经退行性通过调节NRF2-和NF-KB依赖性基因表达以及抑制前炎性NADPH氧化酶-2（NOX-2）活性。然后，我们建议研究临床前模型定义10-NO2-OA在限制PD发病机理中的功效。理由项目是在大脑中建立治疗性10-NO2-OA浓度促进有益的多效组织保护反应，从而代表安全和防止多因素疾病（例如PD）进展的有效药物策略。这该提议的目标是：1）通过该提议定义10-NO2-OA的神经保护潜力 NRF2-和NF-KB依赖性基因表达的调节和Nox-2活性在A中的调节 PD的体外模型，2）评估中脑中10-NO2-OA的PK及其神经保护大鼠PD的烤面包酮模型的影响。成功完成拟议的研究计划通过揭示新的药理学策略来减轻，可以产生重大的积极影响 PD的经济和临床负担。。