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

Immunology. 2018 Jul;154(3):434-451. doi: 10.1111/imm.12893. Epub 2018 Feb 8.

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.

Keywords: autoimmunity; experimental autoimmune encephalomyelitis/multiple sclerosis; neurodegeneration; neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Triphosphate / metabolism
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Biomarkers
  • Cell Line
  • Cytokines / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Female
  • Gene Expression
  • Humans
  • Lovastatin / pharmacology*
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Peroxisomes / drug effects*
  • Peroxisomes / genetics
  • Peroxisomes / metabolism*
  • Peroxisomes / ultrastructure
  • Ribonucleotides / pharmacology
  • Spinal Cord / immunology
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Biomarkers
  • Cytokines
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Adenosine Triphosphate
  • Lovastatin
  • rho-Associated Kinases
  • AMP-Activated Protein Kinases
  • rhoA GTP-Binding Protein
  • AICA ribonucleotide