Combination therapy of lovastatin and AMP‐activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model

Abstract

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.

The peroxisome: an update on mysteries 2.0

“…A combined administration of the statin lovastatin and AICAR to autoimmune encephalomyelitis mice alleviated inflammation-induced dysfunction of mitochondria and peroxisomes as well as demyelination. Thus, restoring peroxisome function might be beneficial for MS disease prognosis (Singh et al 2018 ).…”

Immune modulatory effects of statins

“…9 The study also reported that the metabolite mevalonate is the mediator of training through activation of insulin-like growth factor 1 receptor and mammalian target of rapamycin and subsequent histone modifications in inflammatory pathways. 9 Consistent with a role of statins in immune metabolism, another study reported that lovastatin caused potent protection against inflammationinduced loss and dysfunction of mitochondria and peroxisomes in a mouse model of MS. 10 These different approaches show that statins affect the immune response on multiple layers including signalling, gene transcription, epigenetic modifications and immune metabolism.…”

Metformin as a Potential Agent in the Treatment of Multiple Sclerosis

“…The preclinical studies demonstrated that the combination of lovastatin and AICAR in therapy improved neuroprotection against inflammatory mediators-induced dysfunction in mitochondria and peroxisomes in EAE model [ 74 ]. Furthermore, there is evidence that the supplementation of AICAR with statin combination treatment may provide greater efficacy for MS than statin alone [ 75 ]. Due to insufficient molecular and clinical studies of metformin properties in MS, its effectiveness cannot be unambiguously established.…”