Department of Neurology, Hunan Provincial People's Hospital, The First-affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China.
Clinical Epidemiology Laboratory, Hunan Provincial People's Hospital, The First-affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China.
J Pharm Pharmacol. 2021 Mar 8;73(4):515-521. doi: 10.1093/jpp/rgaa058.
Statins, the most effective lipoprotein-cholesterol lowering drugs, are widely used for patients with cardiovascular disease. The pleiotropic effects of statins have been recently gained attention for their both beneficial and deleterious effects on neurons. We investigated the effects and molecular mechanisms of fluvastatin at clinically relevant concentrations on neuronal cells after induction of oxidative stress.
Both SH-SY5Y, a representative cell line for in vitro neurone model, and human primary neuronal cells were applied. Cellular and biochemical assays were used to investigate the effects of fluvastatin in neurone cells.
Fluvastatin significantly restored H2O2-induced neuronal death in a dose-dependent manner (P < 0.05) and reversed H2O2-induced oxidative stress and damage via restoring mitochondrial function in neuronal cells (P < 0.05). Although fluvastatin inhibited prenylation in neuronal cells, the protective effects of fluvastatin against H2O2-induced neuronal cytotoxicity are not associated with prenylation inhibition or AMPK activation. In contrast, PI3K/Akt/mTOR activation mediated fluvastatin's neuroprotective activity (P < 0.05).
Our work demonstrates the beneficial effects of fluvastatin in neuronal cells under pathological conditions, and, furthermore, this is via prenylation-independent activation of PI3K/Akt/mTOR pathway. Our data highlights the functional significance of the PI3K/Akt/mTOR pathway in neuronal cells in response to oxidative stress.
他汀类药物是最有效的脂蛋白胆固醇降低药物，广泛用于心血管疾病患者。他汀类药物的多效性作用因其对神经元的有益和有害影响而受到关注。我们研究了在诱导氧化应激后，氟伐他汀在临床相关浓度下对神经元细胞的作用及其分子机制。
采用 SH-SY5Y 细胞（一种体外神经元模型的代表性细胞系）和人原代神经元细胞。采用细胞和生化测定法研究氟伐他汀对神经元细胞的作用。
氟伐他汀呈剂量依赖性显著恢复 H2O2 诱导的神经元死亡（P < 0.05），并通过恢复神经元细胞中线粒体功能来逆转 H2O2 诱导的氧化应激和损伤（P < 0.05）。虽然氟伐他汀抑制了神经元中的prenylation，但氟伐他汀对 H2O2 诱导的神经元细胞毒性的保护作用与 prenylation 抑制或 AMPK 激活无关。相反，PI3K/Akt/mTOR 激活介导了氟伐他汀的神经保护活性（P < 0.05）。
我们的工作表明，氟伐他汀在病理条件下对神经元细胞具有有益作用，此外，这是通过不依赖prenylation 的 PI3K/Akt/mTOR 途径激活实现的。我们的数据强调了 PI3K/Akt/mTOR 途径在神经元细胞应对氧化应激中的功能意义。
