Neuroprotective Evaluation of Asiatic Acid in Preclinical Stroke

描述(由申请人提供)： 中风时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、基质金属蛋白酶活性增强、兴奋毒性、细胞凋亡、自由基损伤和小胶质细胞激活的途径。一种“理想的”神经保护剂应该有利于影响多种途径，应该是安全的，耐受性良好，并且应该有很长的治疗时间窗口。亚洲酸是一种植物衍生化合物，已被证明通过其抗谷氨酸、抗氧化和抗炎特性，有利地影响中风中激活的多种有害途径。我们对永久性局灶性脑缺血小鼠的初步研究表明，亚麻酸治疗前后显著缩小梗塞面积，且没有任何明显的毒副作用。根据这一数据和其他公布的数据，亚麻酸可能会成为中风疗法测试的候选药物。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。目前还没有这些数据。这项建议的目标是产生临床前药代动力学、有效性和安全性数据，用于将积雪酸用作中风的神经保护疗法。这些数据将被用来计划更详细的临床前研究，以便将其转化为人体试验。 公共卫生相关性： 在美国，中风是导致死亡和残疾的主要原因之一。FDA批准的唯一治疗方法必须在症状出现后三个小时内进行，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。该项目的目标是对一种名为积雪酸的安全、创新和有前景的天然药物进行临床前评估，因为它在早期临床前中风研究中产生了出色的结果，并有可能使更多的中风患者受益。

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.