Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia.
Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia.
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DOI：
10.1161/strokeaha.111.639427
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发表时间：
2012-06
期刊：
影响因子：
8.3
通讯作者：
Majid A
中科院分区：
文献类型：
--
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
积雪草酸（AA）已被证明可以减轻局灶性缺血小鼠模型中的脑梗死，并显示出作为神经保护性中风治疗的前景。为了便于将这些发现转化为临床研究，我们使用多种卒中模型确定了药代动力学、剂量反应关系、治疗时间窗和疗效。我们还探索了潜在的作用机制。给予递增剂量的静脉内AA，并在药代动力学研究的多个时间点测量血清浓度。随后，确定剂量反应关系，然后在缺血发作后以不同间隔给药，以建立神经保护的治疗时间窗。结果测量包括组织学和行为学。线粒体功能和基质金属蛋白酶活性在对照组和治疗组大鼠进行了测定。药代动力学研究表明，AA（75 mg/kg）的半衰期为2.0小时。即使在缺血发作后12小时的时间点给药，AA也能显著降低梗死体积并改善神经学结局。雌性大鼠和自发性高血压大鼠的脑体积也显著降低。AA减弱线粒体功能障碍和减少基质金属蛋白酶-9诱导。我们的研究表明，AA对多种局灶性缺血模型有效，治疗时间窗长，在雌性和高血压动物中也有效。AA可能通过保护线粒体和抑制基质金属蛋白酶-9的诱导和激活来介导神经保护作用。总之，这些数据表明，AA是一个很好的候选人发展为中风治疗为基础。
Asiatic acid (AA) has been shown to attenuate cerebral infarction in a mouse model of focal ischemia and shows promise as a neuroprotective stroke therapy. To facilitate translation of these findings to clinical studies, we determined pharmacokinetics, a dose response relationship, the therapeutic time window, and efficacy using multiple stroke models. We also explored potential mechanisms of action. Escalating doses of intravenous AA were administered and serum concentrations were measured at multiple time points for the pharmacokinetic studies. Subsequently, a dose response relationship was determined followed by administration at different intervals after the onset of ischemia to establish a therapeutic time window for neuroprotection. Outcome measurements included both histological and behavioral. Mitochondrial function and matrix metalloproteinase activity in controls and treated rats were also determined. The pharmacokinetic studies showed that AA (75mg/kg) has a half life of 2.0 hours. AA significantly decreased infarct volume and improved neurological outcome even when administration at time points up to 12 hours after the onset of ischemia. Infarct volume was also significantly decreased in female rats and spontaneously hypertensive rats. AA attenuated mitochondrial dysfunction and reduced matrix metalloproteinase-9 induction. Our study shows AA is effective against multiple models of focal ischemia, has a long therapeutic time window and is also effective in females and hypertensive animals. AA may mediate neuroprotection by protecting mitochondria and inhibiting matrix metalloproteinase-9 induction and activation. Taken together these data suggest that AA is an excellent candidate for development as a stroke therapy based.