Department of Neurology, Johns Hopkins School of Medicine, Baltimore, USA.
BMC Musculoskelet Disord. 2012 Jun 15;13:100. doi: 10.1186/1471-2474-13-100.
Hmg-CoA reductase inhibitors (statins) are widely used to prevent disease associated with vascular disease and hyperlipidemia. Although side effects are uncommon, clinical observations suggest statin exposure may exacerbate neuromuscular diseases, including peripheral neuropathy and amyotrophic lateral sclerosis. Although some have postulated class-effects, prior studies of hepatocytes and myocytes indicate that the statins may exhibit differential effects. Studies of neuronal cells have been limited.
We examined the effects of statins on cultured neurons and Schwann cells. Cultured spinal motor neurons were grown on transwell inserts and assessed for viability using immunochemical staining for SMI-32. Cultured cortical neurons and Schwann cells were assessed using dynamic viability markers.
7 days of exposure to fluvastatin depleted spinal motor neurons in a dose-dependent manner with a KD of < 2 μM. Profound neurite loss was observed after 4 days exposure in culture. Other statins were found to produce toxic effects at much higher concentrations. In contrast, no such toxicity was observed for cultured Schwann cells or cortical neurons.
It is known from pharmacokinetic studies that daily treatment of young adults with fluvastatin can produce serum levels in the single micromolar range. We conclude that specific mechanisms may explain neuromuscular disease worsening with statins and further study is needed.
羟甲基戊二酰辅酶 A 还原酶抑制剂(他汀类药物)被广泛用于预防与血管疾病和高脂血症相关的疾病。虽然副作用不常见,但临床观察表明他汀类药物的暴露可能会加重神经肌肉疾病,包括周围神经病和肌萎缩侧索硬化症。尽管有人推测存在类效应,但先前对肝细胞和肌细胞的研究表明,他汀类药物可能表现出不同的作用。对神经元细胞的研究有限。
我们研究了他汀类药物对培养神经元和施万细胞的影响。培养的脊髓运动神经元在 Transwell 插入物上生长,并使用 SMI-32 的免疫化学染色评估其活力。使用动态活力标志物评估培养的皮质神经元和施万细胞。
7 天暴露于氟伐他汀以剂量依赖性方式耗尽脊髓运动神经元,KD 值<2μM。在培养 4 天后观察到明显的神经突损失。其他他汀类药物在更高的浓度下产生毒性作用。相比之下,培养的施万细胞或皮质神经元没有观察到这种毒性。
从药代动力学研究可知,对年轻人进行氟伐他汀的每日治疗可产生血清水平在单微摩尔范围内。我们得出结论,特定的机制可能解释了他汀类药物引起的神经肌肉疾病恶化,需要进一步研究。