Rosuvastatin

Rosuvastatin is a competitive HMG-CoA reductase inhibitor with an IC₅₀ value of 11nM^[1]. HMG-CoA reductase is the rate-limiting enzyme in mevalonate biosynthesis, a key step in cholesterol synthesis^[2]. Rosuvastatin potently blocks human ether-a-go-related gene (hERG) currents (IC₅₀=195nM), leading to delayed cardiac repolarization, prolonged action potential duration (APD), and QT interval prolongation (QTc)^[3]. Rosuvastatin effectively reduces low-density lipoprotein (LDL) cholesterol, triglyceride, and C-reactive protein levels^[4].

In vitro, treatment of microglia with Rosuvastatin (1μM) for 6, 24, and 72h significantly inhibited cell proliferation and adhesion, and reduced the expression of pro-inflammatory genes such as IL-1β and TNF-α induced by LPS^[5]. Rosuvastatin (10nM) treatment of human promyelocytic leukemia cells (HL-60 cells) significantly reduced PMA- or hydrogen peroxide-induced DNA damage, decreased reactive oxygen species (ROS) production, and upregulated γ-glutamylcysteine synthetase expression^[6].

In vivo, intravenous administration of Rosuvastatin (0.2mg/kg) to mice with acute stroke significantly reduced brain infarct area 4 hours after middle cerebral artery occlusion (MCAO)^[7].

References:
[1] Watanabe M, Koike H, Ishiba T, et al. Synthesis and biological activity of methanesulfonamide pyrimidine-and N-methanesulfonyl pyrrole-substituted 3, 5-dihydroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors[J]. Bioorganic & medicinal chemistry, 1997, 5(2): 437-444.
[2] Schumacher M M, DeBose-Boyd R A. Posttranslational regulation of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol[J]. Annual review of biochemistry, 2021, 90(1): 659-679.
[3] Plante I, Vigneault P, Drolet B, et al. Rosuvastatin blocks hERG current and prolongs cardiac repolarization[J]. Journal of pharmaceutical sciences, 2012, 101(2): 868-878.
[4] Glynn R J, Koenig W, Nordestgaard B G, et al. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial[J]. Annals of internal medicine, 2010, 152(8): 488-496.
[5] Kata D, Földesi I, Feher L Z, et al. Rosuvastatin enhances anti-inflammatory and inhibits pro-inflammatory functions in cultured microglial cells[J]. Neuroscience, 2016, 314: 47-63.
[6] Schupp N, Schmid U, Heidland A, et al. Rosuvastatin protects against oxidative stress and DNA damage in vitro via upregulation of glutathione synthesis[J]. Atherosclerosis, 2008, 199(2): 278-287.
[7] Prinz V, Laufs U, Gertz K, et al. Intravenous rosuvastatin for acute stroke treatment: an animal study[J]. Stroke, 2008, 39(2): 433-438.

Rosuvastatin是一种竞争性HMG-CoA还原酶抑制剂，IC₅₀值为11nM^[1]。HMG-CoA还原酶是甲羟戊酸生物合成的限速酶，是直接参与胆固醇合成的关键步骤^[2]。Rosuvastatin能够强力阻断人醚-α-Go相关基因（hERG）电流，IC₅₀值为195nM，导致延迟心脏复极化，从而延长动作电位持续时间（APDs）和校正QT间期（QTc）^[3]。Rosuvastatin能够有效降低低密度脂蛋白（LDL）胆固醇、甘油三酯和C反应蛋白水平^[4]。

在体外，Rosuvastatin（1μM）处理小胶质细胞6、24、72h，显著抑制了细胞的增殖和细胞黏附，降低了LPS刺激的细胞内IL-1β、TNF-α等促炎基因的表达^[5]。Rosuvastatin（10nM）处理人类早幼粒细胞（HL-60细胞），显著减少了由佛波醇12-肉豆蔻酸13-乙酸（PMA）或由过氧化氢诱导的DNA损伤，降低了细胞内活性氧的产生，上调了γ-谷氨酰半胱氨酸合成酶的表达^[6]。

在体内，Rosuvastatin（0.2mg/kg）通过静脉注射治疗急性中风模型小鼠，显著降低了丝状中大动脉闭塞（MCAO）后4小时内的脑损伤面积^[7]。