Dimethyl fumarate ameliorates myoclonus stemming from protein misfolding in oligodendrocytes

Abstract

Multiple sclerosis (MS) is considered a primary autoimmune disease; however, this view is increasingly being challenged in basic and clinical science arenas because of the growing body of clinical trials' data showing that exclusion of immune cells from the CNS only modestly slows disease progression to disability. Accordingly, there is significant need for expanding the scope of potential disease mechanisms to understand the etiology of MS. Concomitantly, the use of a broader range of pre-clinical animal models for characterizing existing efficacious clinical treatments may elucidate additional or unexpected mechanisms of action for these drugs that augment insight into MS etiology. Herein, we explore the in vivo mechanism of action of dimethyl fumarate, which has been shown to suppress oxidative stress and immune cell responses in psoriasis and MS. Rather than studying this compound in the context of an experimental autoimmune-induced attack on the CNS, we have used a genetic model of hypomyelination, male rumpshaker (rsh) mice, which exhibit oligodendrocyte metabolic stress and startle-induced subcortical myoclonus during development and into adulthood. We find that myoclonus is reduced 30-50% in treated mutants but we do not detect substantial changes in metabolic or oxidative stress response pathways, cytokine modulation, or myelin thickness (assessed by anova). All procedures involving vertebrate animals in this study were reviewed and approved by the IACUC committee at Wayne State University.

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…Furthermore, a higher number of mature oligodendrocytes was present in a brain-biopsy of a DMF-treated MS patient than in the treatment-naïve biopsies [126] and supernatants from DMF-as well as MMF-treated microglia cultures enhanced the proliferation of OPCs in vitro [135]. However, DMF did not increase the expression of myelin-and oligodendrocyte-related proteins and lipids nor myelin thickness (g-ratio) in hypoperfused mice [123], primary rat oligodendrocyte cultures treated with microglia medium [135] and the mouse rumpshaker hypomyelination model [128].…”

“…Microglial M1 pro-inflammatory status, as measured by the number of IBA1-and CD68-positive cells, was reduced following DMF treatment in hypoperfused mice [123], in OGD-stressed rats [124], LPS-treated mice, vertebral hypoxic ischemia in mice [125], EAE mice [126], the mouse MPTP model of PD [127], rumpshaker hypomyelination mice [128], after spinal cord injury (SCI) in mice [129], ICH in mice [130] and in wild-type mice [131] as well as in mouse primary microglia cultures [132]. Interestingly, DMF increased the number of cluster of differentiation 86 (CD86)-positive microglia in aged rats with streptozotocin-induced AD [133], possibly due to altered inflammatory signaling in aged compared to non-aged microglia [7].…”

“…In the mouse cerebral hypoxic ischemia model, DMF diminished GFAP-positive cells only after 6 h of treatment, but the number of reactive astrocytes increased after 24 h [ 125 ]. However, DMF had no effect on the reduced number of reactive A1 astrocytes in hypomyelinated rumpshaker mice [ 128 ] and the fumaric ester did not induce changes in TNFα, IL-6 and IL-1β expression in LPS- or IFN-y- and IL-1β-stimulated rat primary astrocytes [ 147 ]. Nevertheless, DMF as well as its metabolite MMF, decreased the secretion of pro-inflammatory cytokines such as TNFα, IL-1β, CXCL10 and IL-6 from cultured LPS- or IL-1β-stimulated rodent and human primary astrocytes [ 142 , 148 ], and rat mixed glia and neuron cultures [ 124 ], respectively.…”

“…Furthermore, a higher number of mature oligodendrocytes was present in a brain-biopsy of a DMF-treated MS patient than in the treatment-naïve biopsies [ 126 ] and supernatants from DMF- as well as MMF-treated microglia cultures enhanced the proliferation of OPCs in vitro [ 135 ]. However, DMF did not increase the expression of myelin- and oligodendrocyte-related proteins and lipids nor myelin thickness (g-ratio) in hypoperfused mice [ 123 ], primary rat oligodendrocyte cultures treated with microglia medium [ 135 ] and the mouse rumpshaker hypomyelination model [ 128 ]. Nonetheless, DMF elevated the expression of the myelin-related proteins MBP, PLP, myelin-associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) in cuprizone-fed mice [ 138 ] as well as the number of NPCs positive for the oligodendrocyte marker O4 [ 148 ].…”

Movement Disorder in Demyelinating Disease

“…Various drugs, including carbamazepine, primidone, clonazepam, tizanidine, levetiracetam, baclofen, cannabis, and dimethyl fumarate, have been tried with no significant benefit. [ 32 111 112 113 114 ]…”