Sub-clinical glutamate receptor antagonist combinations prevent progressive demyelination

Summary Multiple sclerosis (MS) affects almost 3 million people globally who suffer demyelination as a series of relapses and remissions that tend towards progressive deterioration over time. The proximate cause is auto-immune attack by the adaptive immune system; therapies directed against this are effective during the relapsing-remitting phase but are less effective or ineffective during progression where other injury mechanisms may be significant. LPS- and cuprizone-induced experimental demyelination share features of progressive demyelination in MS but the underlying mechanisms are not well understood. We show here that these demyelination models can be reproduced ex vivo using short protocols, revealing that combined antagonism of two types of glutamate receptor, NMDA and AMPA, using clinically approved antagonists at sub-clinical doses, can protect against these forms of demyelination. Combined low dose therapy was subsequently shown to be effective in vivo against dietary cuprizone and experimental autoimmune-encephalomyelitis (EAE) models of demyelination and, in particular, protected the smaller myelinated axons that are the main substrate of the function loss in progressive MS.