Objective To investigate the therapeutic efficacy of the fumaric acid ester dimethyl fumarate (DMF) in mouse models of Huntington's disease (HD).
Background The exact sequel of events finally resulting in HD neurodegeneration is only partially understood and there is no established protective treatment so far. Besides immunomodulatory actions and efficacy as disease modifying therapy for multiple sclerosis, DMF potentially exerts neuroprotective effects via induction of ‘nuclear factor E2-related factor 2’ (Nrf2) and detoxification pathways. Thus we investigate the therapeutic efficacy of DMF in the R6/2 and YAC128 mouse model of HD.
Methods 3–5-week-old R6/2 (n=25) and YAC128 mice (n=45) were treated with 0.3 mg DMF orally twice a day or vehicle only. Motor performance was assessed monthly using an accelerating rotarod and graded with a clasping score. Histological analyses of R6/2 mice included immunohistochemistry for Nrf2, huntingtin, microglial activation markers and confocal laser scanning microscopy for NeuN/Nrf2 and GFAP/Nrf2. Neuronal loss was quantified after NeuN and cresyl violet staining.
Results Treatment with DMF significantly prevented weight loss in R6/2 mice between postnatal days 70 and 80 (p<0.0001). At the same time, DMF treatment led to an attenuated motor impairment as measured by the clasping score (0.33±0.15 vs 1.37±0.24, p<0.05). Average survival in the DMF group was 102.3 days versus 97.9 days in the placebo group (p=0.05). Quantification of neuronal densities revealed a significant preservation of intact neurons in the striatum and motor cortex. These results in R6/2 mice were corroborated in a YAC128 cohort where DMF treatment also led to an attenuated motor impairment.
Conclusion In HD mouse models, DMF may exert some beneficial clinical effects and preserves intact neurons. Given its excellent side effect profile, further studies with DMF as a potential neuroprotective approach are warranted in this paradigm.
- dimethyl fumarate