School of Pharmacy and Pharmacology, Griffith University, Queensland 4222, Australia; Quality Use of Medicines Network, Queensland, Australia; Menzies Health Institute Queensland, Griffith University, Queensland, Australia.
Faculty of Health Sciences and Medicine, Bond University, Queensland 4226, Australia.
Toxicol Appl Pharmacol. 2018 Apr 1;344:56-73. doi: 10.1016/j.taap.2018.03.005. Epub 2018 Mar 6.
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been associated with conflicting effects within the central nervous system (CNS), with underlying mechanisms remaining unclear. Although differences between individual statins' CNS effects have been reported clinically, few studies to date have compared multiple statins' neuroprotective effects. This study aimed to compare six statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; 0-100 μM) using an in vitro model of lipopolysaccharide (LPS)-induced neuroinflammation and subsequent neurodegeneration. To achieve this, HAPI microglia were treated with LPS (0.1 μg/mL; 24 h), resulting in increased reactive oxygen species (ROS), nitric oxide, and IL-1β, TNF-α and PGE release. Conditioned media ("HAPI-CM") was then transferred to SH-SY5Y neuroblastoma cells, and effects on cellular viability, mitochondrial membrane permeability, apoptosis, autophagy and ROS production assessed. Of the statins investigated, only atorvastatin, pravastatin and rosuvastatin protected SH-SY5Y cells from LPS-induced decreases in cellular viability; this appeared mediated through reduced caspase 3/7 activation and was associated with decreased IL-1β (atorvastatin, pravastatin) and/or TNF-α (atorvastatin, pravastatin, rosuvastatin). Only pravastatin conferred protection at all tested concentrations. ROS production and autophagic vacuole formation was decreased by all statins, suggesting these two mechanisms are unlikely to be sole mediators of neuroprotection seen with selected statins. Ultimately, our model suggests that despite all statins reducing microglial inflammation, subsequent effects on neuronal viability and cell death signalling pathways varies between statins. Our findings highlight the need to consider individual statins as inducing discrete pharmacological effects within the CNS in future in vitro/in vivo studies and in clinical practice.
3-羟-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂（他汀类药物）在中枢神经系统（CNS）中具有相互矛盾的作用，其潜在机制尚不清楚。尽管临床上已经报道了个体他汀类药物 CNS 作用的差异，但迄今为止，很少有研究比较多种他汀类药物的神经保护作用。本研究旨在使用脂多糖（LPS）诱导的神经炎症和随后的神经退行性变的体外模型比较六种他汀类药物（阿托伐他汀、氟伐他汀、匹伐他汀、普伐他汀、罗苏伐他汀、辛伐他汀；0-100μM）。为了实现这一目标，用 LPS（0.1μg/mL；24 小时）处理 HAPI 小胶质细胞，导致活性氧（ROS）、一氧化氮和 IL-1β、TNF-α 和 PGE 释放增加。然后将条件培养基（“HAPI-CM”）转移到 SH-SY5Y 神经母细胞瘤细胞中，并评估对细胞活力、线粒体膜通透性、细胞凋亡、自噬和 ROS 产生的影响。在所研究的他汀类药物中，只有阿托伐他汀、普伐他汀和罗苏伐他汀能保护 SH-SY5Y 细胞免受 LPS 诱导的细胞活力下降；这似乎是通过降低 caspase 3/7 激活介导的，与降低 IL-1β（阿托伐他汀、普伐他汀）和/或 TNF-α（阿托伐他汀、普伐他汀、罗苏伐他汀）有关。只有普伐他汀在所有测试浓度下都有保护作用。所有他汀类药物均降低 ROS 产生和自噬小泡形成，表明这两种机制不太可能是所选他汀类药物神经保护作用的唯一介导者。最终，我们的模型表明，尽管所有他汀类药物都能减轻小胶质细胞炎症，但随后对神经元活力和细胞死亡信号通路的影响在他汀类药物之间存在差异。我们的研究结果强调了在未来的体外/体内研究和临床实践中，需要考虑个体他汀类药物在中枢神经系统中引起不同的药理学作用。
