Researchers from Ruhr-University Bochum in Germany have reported that a drug currently in clinical trials for multiple sclerosis is neuroprotective in two mouse models of Huntington's disease.
The researchers first examined R6/2 mice at three to four months when they are highly symptomatic and have experienced considerable neurodegeneration. They found that they had significantly more reactive oxygen species (ROS) compared to normal mice, indicating that oxidative stress is associated with the disease. This is consistent with earlier studies. ROS are chemically reactive molecules that form naturally as a byproduct of the metabolism of oxygen in the cell. Under conditions of stress, ROS can increase to a level that overwhelms the cell's defense mechanisms and cause damage to cellular structures.
The researchers then studied the effects of dimethylfumarate, (DMF), a fumaric acid which functions as an antioxidant, when administered to the mice beginning at four weeks of age. They found a trend towards preservation of body weight. Motor impairment was lessened and survival time was increased by seven percent.
The researchers next studied DMF's effects in the YAC128 mice. After a year of treatment, motor impairment was lessened and increased neuronal survival was found compared to untreated mice.
DMF is currently in Phase III clinical trials for relapsing-remitting multiple sclerosis sponsored by Biogen Idec. A Phase IIB trial found a reduction in both lesions and relapses and a good safety profile. According to the company, the mechanism of action is not fully understood but seems likely to be a combination of neuroprotective and anti-inflammatory effects.
Fumaric acid is used as a food additive to make the food more acidic. It is also a component of the citric cycle which converts food to energy in the cell. In addition, it has been used as a treatment for psoriasis for fifty years.
The researchers explored the method of action in the R6/2 mice. Aggregates were unaffected and they did not find an immune system response. They did find an increase in Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in neurons, especially in the striatum and motor cortex. Nrf2 is a transcription factor which regulates the cell's antioxidant response.
The researchers suggest that DMF be pursued as a potential treatment for Huntington's Disease.
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.