Fumaric Acid Esters Attenuate Secondary Degeneration and Promote Functional Recovery Following Experimental Spinal Cord Injury

Abstract

Spinal cord injury (SCI) causes a significant physical, emotional, social and economic burden. The main clinical hallmark of SCI is the permanent loss of motor, sensory and autonomic functions below the level of injury that are in part due to the ensuing inflammatory response. Fumaric acid esters (FAEs) display immunomodulatory properties and may also exert neuroprotective effects, as shown in vitro as well as in experimental models of multiple sclerosis.The aim of the present study was to evaluate the potential beneficial effects of FAE in a mouse model of traumatic spinal cord injury. SCI was induced in mice by spinal cord compression, and dimethyl fumarate (DMF) and monomethyl fumarate (MF) (both at 30 mg/kg) were orally administered to the mice 1 and 6 h after SCI, and once daily thereafter for 10 d. Motor function (Basso Mouse Scale) improved gradually in mice treated with DMF. However, those treated with DMF exhibited a significantly more rapid and sustained recovery of motor function. FAEs also significantly reduced the severity of inflammation (proinflammatory cytokines, apoptosis, and neuroptrophic factors) that characterized the secondary effects of SCI. Again, the effects of DMF were superior to those of MF for several parameters. These results showed marked protective effects of DMF in an animal model of SCI, significantly enhancing recovery of motor function, possibly by reducing the secondary inflammation and tissue injury that characterize this model. In summary, DMF may constitute a promising target for future SCI therapies.