Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Sezione di Biologia Cellulare e Molecolare, Università degli Studi di Perugia, Via del Giochetto, Perugia 06123, Italy.
Eur J Pharmacol. 2011 Jun 25;660(2-3):381-6. doi: 10.1016/j.ejphar.2011.04.002. Epub 2011 Apr 9.
3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors (statins) have been shown to protect against ischemic stroke by mechanisms that are independent of lowering serum cholesterol levels. In this study we investigated the potential neuroprotective effect of a single i.v. treatment with four increasing doses of pravastatin on permanent occlusion of middle cerebral artery (MCAo) in spontaneously hypertensive rats. Pravastatin was given 10 min after MCAo and its effect was determined 24 h later. Treatment results were evaluated in terms of infarct volume, homolateral hemisphere oedema, glial fibrillary acid (GFAP), vimentin (Vim) and endothelial NO synthase (eNOS) immunoreactivity and TUNEL positivity. Cerebral levels of eNOS were measured by western blot analysis. Pravastatin did not reduce cerebral infarct while it mitigated homolateral hemisphere oedema in a dose-dependent manner with respect to controls. No differences among groups were found regarding GFAP and Vim immunoreactivity and TUNEL positivity. Instead, pravastatin-treated animals presented a more marked cerebral eNOS immunoreactivity as compared with controls. In agreement with immunohistochemistry, immunoblot revealed dose-dependent increases in cerebral levels of eNOS in pravastatin rats. Our data confirm statin neuroprotection in cerebral ischemia. In particular, it is of great interest that a single i.v. Pravastatin administration reduced cerebral oedema by upregulating eNOS expression/activity. This, by increasing vascular NO bioavailability, could have produced proximal vasodilation and contributed to reducing perfusional deficit. It is worthy stressing how important the anti-oedema action is that pravastatin seems to exert. Indeed, cerebral oedema, when widespread and beyond limits of physiological compensation, causes endocranic hypertension and additional cerebral damage over time.
3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂（他汀类药物）已被证明可通过独立于降低血清胆固醇水平的机制来预防缺血性中风。在这项研究中，我们研究了单次静脉内给予四种递增剂量普伐他汀对自发性高血压大鼠大脑中动脉永久闭塞（MCAo）的潜在神经保护作用。普伐他汀在 MCAo 后 10 分钟给予，并在 24 小时后评估其效果。治疗结果根据梗塞体积、同侧半球水肿、胶质纤维酸性蛋白（GFAP）、波形蛋白（Vim）和内皮型一氧化氮合酶（eNOS）免疫反应性以及 TUNEL 阳性评估。通过 Western blot 分析测量大脑中的 eNOS 水平。普伐他汀并没有减少脑梗塞，而是以与对照组相比依赖剂量的方式减轻同侧半球水肿。各组之间在 GFAP 和 Vim 免疫反应性和 TUNEL 阳性方面没有差异。相反，与对照组相比，普伐他汀处理的动物表现出更明显的大脑 eNOS 免疫反应性。与免疫组织化学一致，免疫印迹显示普伐他汀大鼠大脑中 eNOS 水平呈剂量依赖性增加。我们的数据证实了他汀类药物在脑缺血中的神经保护作用。特别是，令人感兴趣的是，单次静脉内普伐他汀给药通过上调 eNOS 表达/活性来减轻脑水肿。这通过增加血管中 NO 的生物利用度，可以产生近端血管扩张，并有助于减少灌注缺陷。值得强调的是，普伐他汀似乎发挥的抗水肿作用是多么重要。事实上，当脑水肿广泛且超出生理代偿范围时，会导致颅内压升高，并随着时间的推移导致额外的脑损伤。
