Multiple Sclerosis Drug Metabolite May Slow Parkinson's Disease Onset
Dimethylfumarate could provide a new treatment option for several neurodegenerative diseases.
The oral multiple sclerosis drug dimethylfumarate (DMF) and its metabolite monomethylfumarate (MMF) appeared to significantly slow the onset of Parkinson’s disease during a recent study.
A study published in The Journal of Neuroscience found that MMF more directly targets Nrf2, and could potentially reduce known side effects of the parent drug, especially the gastrointestinal side effects that can aggravate issues already experienced in Parkinson’s disease.
“Nrf2 is a natural protective mechanism we have for oxidative stress,” said researcher Bobby Thomas. “The fact that multiple sclerosis and Parkinson's have in common evidence of declining activity of the Nrf2 pathway has generated interest in the drug for Parkinson's and other neurodegenerative diseases.”
Although MMF is not as potent as DMF in increasing Nrf2 activity, the current study using animal models revealed it is sufficient enough to dramatically slow the loss of dopamine-producing neurons as the parent drug.
Mice were administered the neurotoxin MPTP during the study and had a significant loss of dopamine-producing neurons, with about half lost in only a handful of days. The mice ended up rapidly developing Parkinson’s-like symptoms.
The effects were different in patients who developed symptoms slowly over several years. Once patients seek medical care, they have already lost 30 to 50 of their dopaminergic neurons.
To overcome this hurdle, researchers initially administered mice either DMF or metabolite the day before they started the toxin.
An increase in oxidative stress can cause dopamine to become toxic to neurons. By depleting the natural antioxidant glutathione and reducing the power of mitochondria, DMF causes an increase in oxidative stress, according to the study.
However, brain cell studies have shown that MMF seems to more directly activate Nrf2, increasing glutathione and improving mitochondrial function. Although DMF produces a higher Nrf2 activation, the effect of MMF was sufficient enough to stop the substantial neuron loss within the animal model.
Both MMF and DMF were found to slow neuron loss to a more normal level. The neurons that did survive continued to make dopamine.
Furthermore, oxidative stress levels and inflammation were significantly reduced. Next, researchers will work towards launching a clinical trial of MMF in patients with early Parkinson’s disease.
“If we can catch them early enough, maybe we can slow the disease,” Morgan said. “If it can help give five to eight more years of improved quality of life that would be great for our patients.”