Protective potential of dimethyl fumarate in a mouse model of thalamocortical demyelination

Abstract

Alterations in cortical cellular organization, network functionality, as well as cognitive and locomotor deficits were recently suggested to be pathological hallmarks in multiple sclerosis and corresponding animal models as they might occur following demyelination. To investigate functional changes following demyelination in a well-defined, topographically organized neuronal network, in vitro and in vivo, we focused on the primary auditory cortex (A1) of mice in the cuprizone model of general de- and remyelination. Following myelin loss in this model system, the spatiotemporal propagation of incoming stimuli in A1 was altered and the hierarchical activation of supra- and infragranular cortical layers was lost suggesting a profound effect exerted on neuronal network level. In addition, the response latency in field potential recordings and voltage-sensitive dye imaging was increased following demyelination. These alterations were accompanied by a loss of auditory discrimination abilities in freely behaving animals, a reduction of the nuclear factor-erythroid 2-related factor-2 (Nrf-2) protein in the nucleus in histological staining and persisted during remyelination. To find new strategies to restore demyelination-induced network alteration in addition to the ongoing remyelination, we tested the cytoprotective potential of dimethyl fumarate (DMF). Therapeutic treatment with DMF during remyelination significantly modified spatiotemporal stimulus propagation in the cortex, reduced the cognitive impairment, and prevented the demyelination-induced decrease in nuclear Nrf-2. These results indicate the involvement of anti-oxidative mechanisms in regulating spatiotemporal cortical response pattern following changes in myelination and point to DMF as therapeutic compound for intervention.

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

“…As an α, β-unsaturated carboxylic ester generated by reacting FA with methanol in the presence of sulfuric acid, DMF notably stimulates mitochondrial tricarboxylic acid (TCA) cycle activity and adenosine triphosphate (ATP) production [ 5 ]. Whilst FA alone is poorly absorbed in the gastrointestinal (GI) tract, DMF and its active metabolite monomethyl fumarate (MMF) to which it is almost entirely converted in the gut [ 6 ], have robust bioavailability (for pharmacokinetics data see [ 6 ]) and exert beneficial effects in diseases characterised by inflammation [ 7 , 8 , 9 ], neurodegeneration [ 10 , 11 ] and toxic oxidative stress [ 9 , 12 ]. A modernized version of DMF has recently been developed in diroximel fumarate (DRF), which has comparable efficacy against MS to DMF but with fewer side effects [ 13 ].…”

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

“…As an α, β-unsaturated carboxylic ester generated by reacting FA with methanol in the presence of sulfuric acid, DMF notably stimulates mitochondrial tricarboxylic acid (TCA) cycle activity and adenosine triphosphate (ATP) production [5]. Whilst FA alone is poorly absorbed in the gastrointestinal (GI) tract, DMF and its active metabolite monomethyl fumarate (MMF) to which it is almost entirely converted in the gut [6], have robust bioavailability (for pharmacokinetics data see [6]) and exert beneficial effects in diseases characterised by inflammation [7][8][9], neurodegeneration [10,11] and toxic oxidative stress [9,12].…”

Myelination- and immune-mediated MR-based brain network correlates

“…Pre-clinical studies have reported altered brain tissue properties in animal models of de-and remyelination [16,41,52,90] and in models of experimental autoimmune encephalitis [25,75]. Alterations followed specific regional patterns and occurred within specific temporal scales that were associated with periods of neuroinflammation [11,13,25,75]. However, it remains unclear to which extent network characteristics mirror the level of de-and remyelination or inflammation.…”

“…Loss of myelin alters structure and architecture of neural networks, and hence may have a major impact on brain functioning [35]. The mechanisms underlying such alterations have been partially identified as altered distribution of ion channels following myelin loss [17,44] and alteration of tissue excitability [11,23,24], with subsequent cognitive deficits [11,12,37,80] but not obvious locomotor impairment [80].…”

“…Myelin loss persists as long as cuprizone is added to the diet. When cuprizone is omitted, spontaneous remyelination occurs and control-like levels of myelin are observed after only 3 weeks [11,12,65]. To closely track these dynamics on brain network characteristics and microstructural tissue properties, we investigated de-and remyelination processes in the cuprizone model at different time points by acquiring structural MRI data (including DTI), performing ex-vivo histopathology, and applying behavioral testing.…”