Nrf2-mediated neuroprotective effect of fumaric acid esters in spiral ganglion neurons

To achieve effective treatment of hearing loss using cochlear implants the preservation of spiral ganglion neurons (SGN) is a key goal. As a hallmark of neuronal cell death oxidative stress contributes to the pathology of deafness. Fumaric acid esters (FAEs) are known for their anti-oxidative and neuroprotective properties and the oral application of dimethyl fumarate (DMF) is already an approved treatment for multiple sclerosis. Hence, FAEs represent a promising candidate for SGN neuroprotection.

Here, we investigate the effects of the FAEs dimethyl fumarate (DMF) and monomethyl fumarate (MMF) on SGNs using different mouse cell culture models. S-Nitroso-N-acetylpenicillamin (SNAP) was used as an inducer of oxidative stress and cell death was quantified by propidium iodide (PI) staining and FACS analysis. Gene expression was analyzed by pPCR.

In SGN explant cultures, FAE treatment had no effect on neurite outgrowth. After 24 hours of recovery from oxidative stress 5 µM MMF, 25 µM MMF and 50 µM DMF treatment significantly decreased the percentage of dead cells in a SGN dissociated culture. After 48 hours 25 µM MMF reduced cell death significantly. FAE treatment induced the antioxidative transcription factor nuclear factor E2-related factor 2 (Nrf2) pathway. Relative gene expression of Nrf2 and the downstream detoxifying enzymes heme oxygenase 1 (HO-1) and nicotinamide adenine dinucleotide phosphate quionine oxidoreductase1 (NQO-1) was significantly upregulated in 10 µM and 100 µM DMF or 25 µM MMF treated conditions.

The results demonstrate neuroprotective properties of FAEs and induction of the antioxidative Nrf2 pathway in SGNs. Further research on the effects of FAEs in the auditory system is warranted to offer new therapeutic options for the treatment of hearing loss.

FoRUM der Ruhr-Universität Bochum

Publication History

Article published online:
24 May 2022