Charles P. Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
Research Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC, USA.
Immunology. 2018 Jul;154(3):434-451. doi: 10.1111/imm.12893. Epub 2018 Feb 8.
Recent studies report that loss and dysfunction of mitochondria and peroxisomes contribute to the myelin and axonal damage in multiple sclerosis (MS). In this study, we investigated the efficacy of a combination of lovastatin and AMP-activated protein kinase (AMPK) activator (AICAR) on the loss and dysfunction of mitochondria and peroxisomes and myelin and axonal damage in spinal cords, relative to the clinical disease symptoms, using a mouse model of experimental autoimmune encephalomyelitis (EAE, a model for MS). We observed that lovastatin and AICAR treatments individually provided partial protection of mitochondria/peroxisomes and myelin/axons, and therefore partial attenuation of clinical disease in EAE mice. However, treatment of EAE mice with the lovastatin and AICAR combination provided greater protection of mitochondria/peroxisomes and myelin/axons, and greater improvement in clinical disease compared with individual drug treatments. In spinal cords of EAE mice, lovastatin-mediated inhibition of RhoA and AICAR-mediated activation of AMPK cooperatively enhanced the expression of the transcription factors and regulators (e.g. PPARα/β, SIRT-1, NRF-1, and TFAM) required for biogenesis and the functions of mitochondria (e.g. OXPHOS, MnSOD) and peroxisomes (e.g. PMP70 and catalase). In summary, these studies document that oral medication with a combination of lovastatin and AICAR, which are individually known to have immunomodulatory effects, provides potent protection and repair of inflammation-induced loss and dysfunction of mitochondria and peroxisomes as well as myelin and axonal abnormalities in EAE. As statins are known to provide protection in progressive MS (Phase II study), these studies support that supplementation statin treatment with an AMPK activator may provide greater efficacy against MS.
最近的研究报告称，线粒体和过氧化物酶体的丧失和功能障碍导致多发性硬化症（MS）中的髓鞘和轴突损伤。在这项研究中，我们使用实验性自身免疫性脑脊髓炎（EAE，MS 的模型）小鼠模型，研究了洛伐他汀和 AMP 激活蛋白激酶（AMPK）激活剂（AICAR）联合治疗对脊髓中线粒体和过氧化物酶体以及髓鞘和轴突损伤的丧失和功能障碍的疗效，与临床疾病症状相关。我们观察到，洛伐他汀和 AICAR 单独治疗可部分保护线粒体/过氧化物酶体和髓鞘/轴突，从而部分减轻 EAE 小鼠的临床疾病。然而，与单独药物治疗相比，用洛伐他汀和 AICAR 联合治疗 EAE 小鼠可提供更大的保护线粒体/过氧化物酶体和髓鞘/轴突，以及改善临床疾病。在 EAE 小鼠的脊髓中，洛伐他汀介导的 RhoA 抑制和 AICAR 介导的 AMPK 激活协同增强了转录因子和调节因子（如 PPARα/β、SIRT-1、NRF-1 和 TFAM）的表达，这些转录因子和调节因子是线粒体（如 OXPHOS、MnSOD）和过氧化物酶体（如 PMP70 和过氧化氢酶）发生和功能所必需的。总之，这些研究表明，洛伐他汀和 AICAR 的口服联合用药（单独使用已知具有免疫调节作用）可提供强大的保护和修复作用，可防止炎症引起的线粒体和过氧化物酶体以及 EAE 中的髓鞘和轴突异常的丧失和功能障碍。由于他汀类药物已知在进行性 MS 中提供保护（II 期研究），这些研究支持他汀类药物治疗与 AMPK 激活剂联合使用可能会提高对 MS 的疗效。
