Uekawa Ken, Hasegawa Yu, Ma Mingjie, Nakagawa Takashi, Katayama Tetsuji, Sueta Daisuke, Toyama Kensuke, Kataoka Keiichiro, Koibuchi Nobutaka, Kawano Takayuki, Kuratsu Jun-ichi, Kim-Mitsuyama Shokei
Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
J Stroke Cerebrovasc Dis. 2014 Jul;23(6):1429-39. doi: 10.1016/j.jstrokecerebrovasdis.2013.12.004. Epub 2014 Feb 12.
Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, have been suggested to possess pleiotropic effects, including antioxidant and anti-inflammatory properties. We investigated the protective effects of pretreatment with rosuvastatin, a relatively hydrophilic statin, on early brain injury (EBI) after a subarachnoid hemorrhage (SAH), using the endovascular perforation SAH model.
Eighty-six male Sprague-Dawley rats were randomly divided into 3 groups: (1) sham operation, (2) SAH+vehicle, and (3) SAH+10 mg/kg rosuvastatin. Rosuvastatin or vehicle was orally administered to rats once daily from 7 days before to 1 day after the SAH operation. After SAH, we examined the effects of rosuvastatin on the neurologic score, brain water content, neuronal cell death estimated by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate nick end labeling staining, blood-brain barrier disruption by immunoglobulin G (IgG) extravasation, oxidative stress, and proinflammatory molecules.
Compared with the vehicle group, rosuvastatin significantly improved the neurologic score and reduced the brain water content, neuronal cell death, and IgG extravasation. Rosuvastatin inhibited brain superoxide production, nuclear factor-kappa B (NF-κB) activation, and the increase in activated microglial cells after SAH. The increased expressions of tumor necrosis factor-alpha, endothelial matrix metalloproteinase-9, and neuronal cyclooxygenase-2 induced by SAH were prevented by rosuvastatin pretreatment.
The present study demonstrates that rosuvastatin pretreatment ameliorates EBI after SAH through the attenuation of oxidative stress and NF-κB-mediated inflammation.
他汀类药物，即3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，已被认为具有多效性作用，包括抗氧化和抗炎特性。我们使用血管内穿刺蛛网膜下腔出血（SAH）模型，研究了相对亲水性的他汀类药物瑞舒伐他汀预处理对SAH后早期脑损伤（EBI）的保护作用。
86只雄性Sprague-Dawley大鼠随机分为3组：（1）假手术组，（2）SAH+溶剂组，（3）SAH+10mg/kg瑞舒伐他汀组。从SAH手术前7天至手术后1天，每天给大鼠口服一次瑞舒伐他汀或溶剂。SAH后，我们检测了瑞舒伐他汀对神经功能评分、脑含水量、通过末端脱氧核苷酸转移酶介导的尿苷5'-三磷酸缺口末端标记染色评估的神经元细胞死亡、免疫球蛋白G（IgG）外渗导致的血脑屏障破坏、氧化应激和促炎分子的影响。
与溶剂组相比，瑞舒伐他汀显著改善了神经功能评分，降低了脑含水量、神经元细胞死亡和IgG外渗。瑞舒伐他汀抑制了SAH后脑超氧化物的产生、核因子-κB（NF-κB）的激活以及活化小胶质细胞的增加。SAH诱导的肿瘤坏死因子-α、内皮基质金属蛋白酶-9和神经元环氧化酶-2的表达增加被瑞舒伐他汀预处理所抑制。
本研究表明，瑞舒伐他汀预处理通过减轻氧化应激和NF-κB介导的炎症来改善SAH后的EBI。
