Pitavastatin

Pitavastatin is a 3-Hydroxymethyl-3-glutaryl-CoA (HMG-CoA) reductase inhibitors. The IC₅₀ value of the HMG-CoA reductase activity in the Hep G2 cells for Pitavastatin was 5.8nM^[1]. Pitavastatin is clinically employed as an oral statin to lower LDL-cholesterol and prevent cardiovascular events, while also exerting anti-atherosclerotic, anti-asthmatic, anti-osteoarthritis, antineoplastic, neuroprotective, hepatoprotective and reno-protective effects^[2][3].

In vitro, M1C transfectant cell line derived from human neuroblastoma BE(2)-M17D cells were exposed to Pitavastatin (0.5, 1, 2, 5, or 10μM) for 0.5, 1, 1.5, 2, or 4 days. Pitavastatin caused a dose-dependent reduction of both total and phosphorylated tau without affecting tau mRNA or cell viability. Maximal clearance was achieved after 36h of 1µM treatment^[4]. Human saphenous vein endothelial cells were incubated with 0.1μM or 1μM of Pitavastatin for an hour followed by induction of inflammation by TNF-α. Pitavastatin increased ICAM-1 mRNA expression but did not significantly alter the relative mRNA leve of NF-κB. High-dose Pitavastatin is more cytoprotective since lower LDH levels were obtained in the group of high-dose Pitavastatin compared to low-dose Pitavastatin^[5]. Ovarian cancer Ovcar-8 or Ovcar-3 cells were exposed to Pitavastatin (1μM) for 48h. Pitavastatin inhibited the growth of cultures of ovarian cancer cells evidenced by the increased activity of executioner caspases-3,7 as well as caspase-8 and caspase-9 in two separate cell lines, and induced PARP cleavage^[6].

In vivo, 10 oophorectomized female rabbits were fed with regular diet with or without Pitavastatin (0.1mg/kg per day) for 12 weeks. Pitavastatin retarded the progression of atherosclerosis formation and it improved NO bioavailability by eNOS up-regulation and decrease of O₂^−[7]. Experimental autoimmune myocarditis (EAM) mouse models were fed Pitavastatin (5mg/kg) or vehicle once daily by gavage feeding for 3 weeks. Pitavastatin ameliorated EAM by inhibiting the phosphorylation of signal transducer and activator of transcription STAT3 and STAT4 and suppressing production of Th1 cytokine interferon-γ and Th17 cytokine interleukin-17 from autoreactive CD4⁺ T cells^[8].

References:
[1] Morikawa S, Umetani M, Nakagawa S, et al. Relative induction of mRNA for HMG CoA reductase and LDL receptor by five different HMG-CoA reductase inhibitors in cultured human cells. J Atheroscler Thromb. 2000;7(3):138-44. 
[2] Masana L. Pitavastatin in cardiometabolic disease: therapeutic profile. Cardiovasc Diabetol. 2013 May 30;12(Suppl 1):S2.
[3] Sahebkar A, Kiaie N, Gorabi A M, et al. A comprehensive review on the lipid and pleiotropic effects of Pitavastatin. Prog Lipid Res. 2021 Nov;84:101127.
[4] Hamano T, Yen S H, Gendron T, et al. Pitavastatin decreases tau levels via the inactivation of Rho/ROCK. Neurobiol Aging. 2012 Oct;33(10):2306-20.
[5] Demir B, Onal B, Ozyazgan S, et al. The Effects of Pitavastatin on Nuclear Factor-Kappa B and ICAM-1 in Human Saphenous Vein Graft Endothelial Culture. Cardiovasc Ther. 2019 May 2:2019:2549432.
[6] Wolf E, Abdullah M I, Jones S M, et al. Dietary geranylgeraniol can limit the activity of Pitavastatin as a potential treatment for drug-resistant ovarian cancer. Sci Rep. 2017 Jul 14;7(1):5410. 
[7] Hayashi T, Rani J A P, Fukatsu A, et al. A new HMG-CoA reductase inhibitor, Pitavastatin remarkably retards the progression of high cholesterol induced atherosclerosis in rabbits. Atherosclerosis. 2004 Oct;176(2):255-63.
[8] Tajiri K, Shimojo N, Sakai S, et al. Pitavastatin regulates helper T-cell differentiation and ameliorates autoimmune myocarditis in mice. Cardiovasc Drugs Ther. 2013 Oct;27(5):413-24.

Pitavastatin是一种3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，在Hep G2细胞中对HMG-CoA还原酶活性的IC₅₀值为5.8nM^[1]。Pitavastatin临床用作口服他汀类药物，以降低LDL胆固醇并预防心血管事件，同时发挥抗动脉粥样硬化、抗哮喘、抗骨关节炎、抗肿瘤、神经保护、肝脏保护和肾脏保护作用^[2][3]。

体外实验中，将来源于人神经母细胞瘤BE(2)-M17D细胞的M1C转染细胞系暴露于0.5、1、2、5或10μM的Pitavastatin，处理0.5、1、1.5、2或4天。Pitavastatin呈剂量依赖性降低总tau和磷酸化tau水平，而不影响tau mRNA表达水平或细胞活力；在1µM处理36h后tau清除达到最大^[4]。将人隐静脉内皮细胞与0.1μM或1μM的Pitavastatin孵育1h，随后用TNF-α诱导炎症。Pitavastatin增加ICAM-1 mRNA表达，但对NF-κB mRNA水平无显著影响；高剂量Pitavastatin的细胞保护作用更强，因高剂量处理的细胞LDH水平低于低剂量组^[5]。将卵巢癌细胞系Ovcar-8或Ovcar-3暴露于1μM的Pitavastatin 48h。Pitavastatin抑制卵巢癌细胞生长，表现为两种细胞系中执行型caspase-3,7、caspase-8和caspase-9活性升高，并诱导PARP裂解^[6]。

体内实验中，10只卵巢切除雌兔给予常规饲料或含Pitavastatin（0.1mg/kg/day）饲料12周。Pitavastatin延缓动脉粥样硬化进展，并通过上调eNOS及降低O₂⁻提高NO生物利用度^[7]。实验性自身免疫性心肌炎（EAM）小鼠模型每日一次经口灌胃给予Pitavastatin（5mg/kg）或溶媒，持续3周。Pitavastatin通过抑制信号转导与转录激活因子STAT3和STAT4的磷酸化，并抑制自身反应性CD4⁺ T细胞产生Th1细胞因子干扰素-γ和Th17细胞因子白细胞介素-17，从而减轻EAM^[8]。