Abstract
While great advances have been made in the immunomodulatory treatment of multiple sclerosis (MS), there is still an unmet need for drugs with neuroprotective potential. Dimethyl fumarate (DMF) has been suggested to exert both immunomodulatory and neuroprotective effects in MS. To investigate if DMF has neuroprotective effects independent of immunomodulation we evaluated its effects in the non-inflammatory animal models of light-induced photoreceptor loss and optic nerve crush. This might also reveal applications for DMF besides MS, such as age related macular degeneration. Retinal neurodegeneration was longitudinally assessed by in vivo retinal imaging using optical coherence tomography (OCT), and glutathione (GSH) measurements as well as histological investigations were performed to clarify the mode of action. For light-induced photoreceptor loss, one eye of C57BL/6J mice was irradiated with a LED cold light lamp while for optic nerve crush the optic nerve was clamped behind the eye bulb. The other eye served as control. GSH was measured in the optic nerve, choroid and retina and immunohistological staining of retinal microglia (Iba1) was performed. Mice were treated with 15 or 30 mg DMF/kg bodyweight or vehicle. While no protective effects were observed in optic nerve crush, in the light-induced retinal degeneration model DMF treatment significantly reduced retinal degeneration. In these mice, GSH levels in the retina and surrounding choroid were increased and histological investigations revealed less microglial activation in the outer retinal layers, suggesting both antioxidant and anti-inflammatory effects.
Highlights
There is an urgent unmet need for new therapeutic approaches effectively preventing the chronic progression of disability and promoting repair in autoimmune diseases of the central nervous system like multiple sclerosis (MS) [1]
The measurement revealed that the optic nerve crush led to a strong degeneration of the inner retinal layer (IRL) (Figures 1A,C) and a decrease of the total retinal thickness
We found an elevated level of the antioxidant GSH in the optic nerve of mice treated with 30 mg/kg body weight (BW) Dimethyl fumarate (DMF), while 15 mg/kg did not significantly increase GSH
Summary
There is an urgent unmet need for new therapeutic approaches effectively preventing the chronic progression of disability and promoting repair in autoimmune diseases of the central nervous system like multiple sclerosis (MS) [1]. Fumaric acid esters including dimethyl fumarate (DMF) have previously been used to treat autoimmune disorders like psoriasis and arthritis, where they exert anti-inflammatory effects [2]. Neuroprotective Properties of Dimethyl Fumarate [5, 6] and has been approved as a disease-modifying therapy for the treatment of relapsing MS. DMF and other fumaric esters have been reported to induce a shift from “Th1” cytokines (IL-2, TNF-α, IFN-γ) to “Th2” cytokines (IL-4, IL-5) as part of their treatment effect in human psoriasis. These effects were reported to be due to inhibition of the NF-κB pathway [7]
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