Abstract
Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understood and there is no established protective treatment so far. Some lines of evidence speak for the contribution of oxidative stress to neuronal tissue damage. The fumaric acid ester dimethylfumarate (DMF) is a new disease modifying therapy currently in phase III studies for relapsing-remitting multiple sclerosis. DMF potentially exerts neuroprotective effects via induction of the transcription factor “nuclear factor E2-related factor 2” (Nrf2) and detoxification pathways. Thus, we investigated here the therapeutic efficacy of DMF in R6/2 and YAC128 HD transgenic mice which mimic many aspects of HD and are characterized by an enhanced generation of free radicals in neurons. Treatment with DMF significantly prevented weight loss in R6/2 mice between postnatal days 80–90. At the same time, DMF treatment led to an attenuated motor impairment as measured by the clasping score. Average survival in the DMF group was 100.5 days vs. 94.0 days in the placebo group. In the histological analysis on day 80, DMF treatment resulted in a significant preservation of morphologically intact neurons in the striatum as well as in the motor cortex. DMF treatment resulted in an increased Nrf2 immunoreactivity in neuronal subpopulations, but not in astrocytes. These beneficial effects were corroborated in YAC128 mice which, after one year of DMF treatment, also displayed reduced dyskinesia as well as a preservation of neurons. In conclusion, DMF may exert beneficial effects in mouse models of HD. Given its excellent side effect profile, further studies with DMF as new therapeutic approach in HD and other neurodegenerative diseases are warranted.
Highlights
Huntington’s Disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a trinucleotide CAG repeat expansion $36 in the HD gene located on chromosome 4
Since we found a considerable amount of oxidative stress in the R6/2 mouse model of HD, we were interested in the clinical effects of DMF, a compound which has been recently shown to exert neuroprotective effects via the induction of antioxidant pathways [6]
Upon comparison of DMF treated R6/2 mice with controls treated with carrier solution alone, there was a trend to preserved body weight after DMF treatment with a significant preservation of body weight on days 85 and 90 of life (Fig. 2A)
Summary
Huntington’s Disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a trinucleotide CAG repeat expansion $36 in the HD gene located on chromosome 4. The course of HD is characterized by progressive motor dysfunction, cognitive impairment, affective disorders and personality changes. The most striking neuropathological feature of HD is the progressive atrophy of the striatum and cortex accompanied by neuronal cell loss in these regions [1]. The major histopathological hallmark is the accumulation of intracellular huntingtin (Htt) aggregates, which continuously increase as the disease progresses. The underlying mechanisms of neurodegeneration and Htt aggregation are far less well understood. Lack of trophic factors, mitochondrial dysfunction and oxidative stress may play a role [2]. Therapeutic options for HD are limited to symptomatic treatment approaches and there is no cure for this devastating disease
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