Neuroprotective Properties of Dimethyl Fumarate Measured by Optical Coherence Tomography in Non-inflammatory Animal Models

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.

Dimethyl Fumarate Blocks Tumor Necrosis Factor-Alpha-Driven Inflammation and Metabolic Rewiring in the Retinal Pigment Epithelium

“…The anti-inflammatory capacity of DMFu showed beneficial effects in an autoimmune uveitis rat model ( Labsi et al, 2021 ) and optic neuritis murine model ( Zyla et al, 2019 ). Further, DMFu promotes the survival of retinal ganglion cells (RGCs) after optic nerve crush ( Mori et al, 2020 ) and protects against retinal degeneration in a light-induced photoreceptor loss mouse model ( Dietrich et al, 2020 ). Mechanistically, studies have shown that DMFu activates Nrf2/heme oxygenase-1 (HO-1) ( Zyla et al, 2019 ; Mori et al, 2020 ) and increases glutathione ( Nelson et al, 1999 ; Dietrich et al, 2020 ) to mediate its anti-inflammatory and anti-oxidative effects.…”

“…Further, DMFu promotes the survival of retinal ganglion cells (RGCs) after optic nerve crush ( Mori et al, 2020 ) and protects against retinal degeneration in a light-induced photoreceptor loss mouse model ( Dietrich et al, 2020 ). Mechanistically, studies have shown that DMFu activates Nrf2/heme oxygenase-1 (HO-1) ( Zyla et al, 2019 ; Mori et al, 2020 ) and increases glutathione ( Nelson et al, 1999 ; Dietrich et al, 2020 ) to mediate its anti-inflammatory and anti-oxidative effects. Intriguingly, in this study, DMFu alone induces significant metabolic changes compared to DMSO-treated control cells.…”

Dimethyl Fumarate Triggers the Antioxidant Defense System in Human Retinal Endothelial Cells through Nrf2 Activation

“…Indeed, previous in vitro studies on DMF effects in primary endothelial cells were carried out in human umbilical vascular endothelial cells (HUVEC) [ 24 ] and human brain microvascular endothelial cells (HBMVEC) [ 61 ]. By far, the potential role of DMF and its derivatives as protective agents for retinal diseases has received little attention [ 62 , 63 ]; our findings give a new impulse to this perspective and go further, suggesting that DMF can be repurposed in eye pathologies involving alterations of the endothelium and, more extensively, in ocular diseases characterized by oxidative stress and inflammation.…”

Semi-Automated Live Tracking of Microglial Activation in CX3CR1GFP Mice During Experimental Autoimmune Encephalomyelitis by Confocal Scanning Laser Ophthalmoscopy

“…A detailed protocol can be found in the Supplementary Material . In brief, the eyes were dissected from 6 representative animals per group 12 weeks after immunization and processed as previously described ( 35 ). After paraffin embedding, eyes were longitudinally sectioned at 5 µm and stained with Iba1 (1:500, Wako chemicals) and Cy5 anti-rabbit (1:500, Millipore) as secondary antibody.…”