Premium
Combination therapy of lovastatin and AMP ‐activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model
Author(s) -
Singh Inderjit,
Samuvel Devadoss J.,
Choi Seungho,
Saxeishant,
Singh Avtar K.,
Won Jeseong
Publication year - 2018
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12893
Subject(s) - experimental autoimmune encephalomyelitis , lovastatin , mitochondrion , ampk , biology , myelin , peroxisome , protein kinase a , multiple sclerosis , pharmacology , microbiology and biotechnology , immunology , endocrinology , kinase , biochemistry , receptor , central nervous system , cholesterol
Summary 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. PPAR α / β , SIRT ‐1, NRF ‐1, and TFAM ) required for biogenesis and the functions of mitochondria (e.g. OXPHOS , Mn SOD ) and peroxisomes (e.g. PMP 70 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 .