Combination therapy with fenofibrate, a peroxisome proliferator-activated receptor α agonist, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor, on experimental traumatic brain injury
Combination therapy with fenofibrate, a peroxisome proliferator-activated receptor α agonist, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor, on experimental traumatic brain injury
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DOI：
10.1124/jpet.108.140368
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发表时间：
2008-09-01
影响因子：
3.5
通讯作者：
Marchand-Leroux, Catherine
中科院分区：
文献类型：
--
作者：
Chen, Xiao Ru;Besson, Valerie C.;Marchand-Leroux, Catherine
我们和其他人已经证明贝特类[过氧化物酶体增殖物激活受体（PPAR）α激动剂]和他汀类药物（3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂）在创伤性脑损伤（TBI）的实验模型中发挥神经保护和多效性作用。因为他汀类药物和贝特类药物的组合协同增强了PPAR α激活，我们假设这两种药物的组合可能比单独使用在TBI中发挥更重要和/或更长的有益作用。在这项研究中，我们研究了非诺贝特与辛伐他汀的组合，在损伤后1和6小时，对TBI的后果。首先，我们的剂量效应研究表明，最有效的剂量辛伐他汀（37.5毫克/公斤）减少创伤后神经功能缺损和脑水肿。然后，观察非诺贝特（50 mg/kg）和辛伐他汀（37.5 mg/kg）联合给药的作用。分别于伤后1 h和6 h观察TBI早期和晚期的临床疗效。与单药治疗相比，联合治疗具有更持久的促进神经恢复和抗水肿作用，并协同减少创伤后脑损伤。此外，延迟治疗给予p.o.脑损伤后3、8h联合用药对脑损伤后神经功能缺损仍有明显改善作用，但48 h时对脑水肿无明显改善作用。目前的数据代表了第一次证明，非诺贝特和辛伐他汀的组合发挥长期和协同的神经保护作用比每种药物单独使用。因此，这些结果可能对TBI的治疗具有重要的治疗意义。
We and others have demonstrated that fibrates [peroxisome proliferator-activated receptor (PPAR)alpha agonists] and statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) exerted neuroprotective and pleiotropic effects in experimental models of traumatic brain injury (TBI). Because the combination of statins and fibrates synergistically enhanced PPAR alpha activation, we hypothesized that the combination of both drugs may exert more important and/or prolonged beneficial effects in TBI than each alone. In this study, we examined the combination of fenofibrate with simvastatin, administered 1 and 6 h after injury, on the consequences of TBI. First, our dose-effect study demonstrated that the most efficient dose of simvastatin (37.5 mg/kg) reduced post-traumatic neurological deficits and brain edema. Then, the effects of the combination of fenofibrate (50 mg/kg) and simvastatin (37.5 mg/kg), given p. o. at 1 and 6 h after TBI, were evaluated on the TBI consequences in the early and late phase after injury. The combination exerted more sustained neurological recovery-promoting and antiedematous effects than monotherapies, and it synergistically decreased the post-traumatic brain lesion. Furthermore, a delayed treatment given p. o. at 3 and 8 h after TBI with the combination was still efficient on neurological deficits induced by TBI, but it failed to reduce the brain edema at 48 h. The present data represent the first demonstration that the combination of fenofibrate and simvastatin exerts prolonged and synergistic neuroprotective effects than each drug alone. Thus, these results may have important therapeutic significance for the treatment of TBI.