Simvastatin improves clinical scores in a rabbit multiple infarct ischemic stroke model: synergism with a ROCK inhibitor but not the thrombolytic tissue plasminogen activator.
Simvastatin improves clinical scores in a rabbit multiple infarct ischemic stroke model: synergism with a ROCK inhibitor but not the thrombolytic tissue plasminogen activator.
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DOI：
10.1016/j.brainres.2010.05.035
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发表时间：
2010-07-16
期刊：
影响因子：
2.9
通讯作者：
Han, Moon Ku
中科院分区：
文献类型：
--
作者：
Lapchak, Paul A.;Han, Moon Ku
他汀类药物在中枢神经系统中具有多效性神经保护作用。在这项研究中，我们评估了辛伐他汀对新西兰白色家兔行为指标的药理学作用，该家兔使用小尺寸血栓混悬液进行栓塞。对于这些研究，在栓塞后3小时内给予辛伐他汀，并在栓塞后48小时测量行为，以计算在50%家兔中产生神经功能缺损的栓子剂量（P50，mg）。如果与对照相比显著增加P50，则认为治疗具有神经保护作用。辛伐他汀治疗（20 mg/kg，皮下推注）在栓塞后1小时显著改善了临床功能，并使P50增加了143%，但在3小时无效。在使用3.3 mg/kg（20%推注，80%输注）标准静脉剂量的溶血栓组织纤溶酶原激活剂（tPA）的联合研究中，我们发现辛伐他汀可以安全地与tPA一起给药以改善临床评分，但是联合治疗的最大行为改善与单独单药治疗相似，两者均显著改善行为（p<0.05）。辛伐他汀的神经保护作用可能与包括Rho激酶（ROCK）在内的多种信号通路有关。为了确定ROCK机制是否参与辛伐他汀诱导的栓塞性卒中后的神经保护，我们使用了ROCK抑制剂法舒地尔进行药物干预。当法舒地尔在辛伐他汀给药前30分钟给药（1小时给药）时，行为功能有额外的显著（p=0.0217）协同增加。然而，法舒地尔作为单药治疗并不影响栓塞兔的行为功能。该研究表明，辛伐他汀治疗与ROCK信号通路之间可能存在相互作用，应进一步探讨。我们的研究结果表明，辛伐他汀治疗可能有临床效益时，单独使用或在tPA的存在下，但使用单剂量方案的治疗窗口是狭窄的。
Statins have pleiotropic neuroprotective effects in the central nervous system. In this study, we assessed the pharmacological effects of simvastatin on measures of behavior in New Zealand white rabbits embolized using a suspension of small-sized blood clots. For these studies, simvastatin was administered up to 3 hours following embolization, and behavior was measured 48 hours following embolization in order to calculate the dose of emboli (P50 in mg) that produces neurological deficits in 50% of the rabbits. A treatment is considered neuroprotective if it significantly increases the P50 compared to control. Simvastatin treatment (20mg/kg, bolus subcutaneous injection) significantly improved clinical function and increased the P50 by 143% when administered 1 hour following embolization, but was ineffective at 3 hours. In combination studies with the thrombolytic, tissue plasminogen activator (tPA) using a standard intravenous dose of 3.3 mg/kg (20% bolus, 80% infused), we found that simvastatin could be safely administered with tPA to improve clinical scores, however the maximum behavioral improvement with the combination treatment was similar to either monotherapy alone, both of which significantly improved behavior (p<0.05). It has been proposed that Simvastatin neuroprotection may be related to a variety of signaling pathways including Rho-kinase (ROCK). To determine if a ROCK mechanism is involved in simvastatin-induced neuroprotection following embolic strokes, we used pharmacological intervention with the ROCK inhibitor, FASUDIL. When FASUDIL was administered 30 minutes prior to simvastatin (given at 1 hour), there was an additional significant (p=0.0217) synergistic increase in behavioral function. However, FASUDIL as a monotherapy did not affect behavioral function in embolized rabbits. The study suggests that there may be an interaction between simvastatin treatment and the ROCK signaling pathway that should be further explored. Our results suggest that simvastatin treatment may have clinical benefit when used alone or in the presence of tPA, but the therapeutic window using a single dose regimen is narrow.
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