Neuroprotective Evaluation of Asiatic Acid in Preclinical Stroke

亚洲酸在临床前卒中中的神经保护作用评价

• 批准号: 7846748
• 负责人: ARSHAD MAJID
• 金额: $ 18.81万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846748
• 关键词: Adverse effects; Aftercare; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Cause of Death; Cell Death; Cerebral Ischemia; Cerebrum; Data; Dose; Drug Kinetics; Evaluation; Event; FDA approved; Free Radicals; Glutamates; Goals; Hospitals; Hour; Human; Infarction; Inflammation; Injury; Interruption; Lead; Matrix Metalloproteinases; Modeling; Mus; Neuroprotective Agents; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Plants; Process; Property; Publishing; Rattus; Role; Safety; Stroke; Symptoms; Testing; Therapeutic; Time; Translations; United States; asiatic acid; base; disability; excitotoxicity; innovation; intravenous administration; neuroprotection; pre-clinical; preclinical study; public health relevance; research clinical testing; response; stroke therapy

DESCRIPTION (provided by applicant): Cellular damage during stroke occurs via multiple and diverse pathways. There are considerable data implicating the pathways of secondary inflammation, enhanced matrix metalloproteinase activity, excitotoxicity, apoptosis, free radical injury, and microglial activation. An "ideal" neuroprotectant should favorably influence multiple pathways, should be safe and well tolerated, and should have a long therapeutic time window. Asiatic acid is a plant-derived compound that has been shown to favorably influence multiple deleterious pathways that are activated in stroke through its anti- glutamate, anti-oxidant and anti-inflammatory properties. Our preliminary studies in mice subjected to permanent focal cerebral ischemia suggest that pre-treatment and post-treatment with asiatic acid significantly reduces infarct size without any obvious toxic side effects. Based on this and other published data, asiatic acid could emerge as a candidate for testing as a stroke therapy. However, before clinical testing can take place, rigorous and extensive preclinical pharmacokinetic, safety and efficacy data is required. These data are not available at this time. The goal of this proposal is to generate preclinical pharmacokinetic, efficacy and safety data for the use of asiatic acid as a neuroprotective therapy in stroke. These data will be used to plan more detailed preclinical studies that will allow translation to human testing. PUBLIC HEALTH RELEVANCE: Stroke is one of the leading causes of death and disability in the United States. The only approved FDA therapy must be administered within three hours of symptom onset but most stroke victims are not eligible for this treatment because they arrive in hospital too late. The goal of this project is to evaluate pre-clinically, a safe, innovative and promising natural drug called asiatic acid, because it has produced excellent results in early preclinical stroke studies and has the potential to benefit many more stroke patients.

描述（由申请人提供）： 中风期间的细胞损伤通过多种不同的途径发生。有相当多的数据涉及继发性炎症，增强基质金属蛋白酶活性，兴奋性毒性，细胞凋亡，自由基损伤和小胶质细胞活化的途径。“理想的”神经保护剂应该有利地影响多个途径，应该是安全的和良好的耐受性，并且应该具有长的治疗时间窗。积雪草酸是一种植物来源的化合物，已显示其通过其抗谷氨酸、抗氧化剂和抗炎特性有利地影响中风中激活的多种有害途径。我们在小鼠永久性局灶性脑缺血中的初步研究表明，积雪草酸的预处理和后处理显着减少梗死面积，没有任何明显的毒副作用。基于这一点和其他已发表的数据，积雪草酸可能成为测试中风治疗的候选药物。然而，在进行临床试验之前，需要严格和广泛的临床前药代动力学，安全性和有效性数据。这些数据目前不可用。本提案的目的是为积雪草酸作为脑卒中的神经保护治疗提供临床前药代动力学、疗效和安全性数据。这些数据将用于计划更详细的临床前研究，以便转化为人体试验。 公共卫生关系： 中风是美国死亡和残疾的主要原因之一。FDA唯一批准的治疗必须在症状发作后三小时内进行，但大多数中风患者没有资格接受这种治疗，因为他们到达医院太晚了。该项目的目标是在临床前评估一种名为积雪草酸的安全，创新和有前途的天然药物，因为它在早期临床前中风研究中取得了优异的结果，并有可能使更多的中风患者受益。

项目成果

Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia.

• DOI: 10.1161/strokeaha.111.639427
• 发表时间: 2012-06
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Lee KY;Bae ON;Serfozo K;Hejabian S;Moussa A;Reeves M;Rumbeiha W;Fitzgerald SD;Stein G;Baek SH;Goudreau J;Kassab M;Majid A
• 通讯作者: Majid A