MS drug metabolite may be effective therapy for Parkinson's

The metabolite of a drug that helps patients battle multiple sclerosis appears to significantly slow the onset of Parkinson's disease, a new study has claimed.
The oral drug, dimethylfumarate, or DMF, and its metabolite, monomethylfumarate, or MMF, both increase activity of Nrf2, a protein that helps protect the body from oxidative stress and inflammation, hallmarks of both diseases, according to Bobby Thomas from Augusta University in the US.
The study provides the first evidence that the metabolite, which is essentially the active portion of the parent drug, more directly targets Nrf2, potentially reducing known side effects of the parent drug that include flushing, diarrhea, nausea, vomiting, abdominal pain and the brain infection encephalopathy, said Thomas.

"Particularly, the gastrointestinal side effects can exacerbate some problems patients with Parkinson's already experience," added John Morgan from Augusta University.
In addition to destroying neurons in the brain that produce dopamine, a neurotransmitter that enables movement and learning, Parkinson's causes nerve cell death in the gastrointestinal tract and related problems such as severe constipation.
"Nrf2 is a natural protective mechanism we have for oxidative stress. 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," said Thomas.

DMF was approved for multiple sclerosis three years ago. While its metabolite MMF is not quite as potent as the parent drug in increasing Nrf2 activity, the new study indicates that its action is sufficient to dramatically slow the loss of dopamine-producing neurons as well as the parent drug, in an animal model of Parkinson's.

In their model, mice given the neurotoxin MPTP experience a dramatic loss of dopamine-producing neurons, losing about half within a handful of days, and rapidly develop Parkinson's-like symptoms. Patients, on the other hand, slowly develop symptoms over many years.
"By the time they seek medical care, patients may have lost 30-50 per cent of their dopaminergic neurons," said Morgan.
To accommodate the very compressed timeline in their model and the fact that several daily doses are needed before the drug starts to work, researchers first gave the mice either the drug or metabolite the day before they started the toxin.

The metabolite MMF appears to more directly activate Nrf2, and actually increases glutathione and improves mitochondrial function, brain cell studies showed.
While the parent drug ultimately produces a higher Nrf2 activation, the researchers found the MMF effect was sufficient to stop the dramatic neuron loss in the animal model.
The findings were published in The Journal of Neuroscience.