An FDA-approved drug for high blood pressure alleviates clinical symptoms of MS in mice, showing great promise for humans.
Guanabenz, a drug that is FDA-approved for high blood pressure, also prevents myelin loss and alleviates clinical symptoms of multiple sclerosis (MS), according to a new study.
The drug appears to enhance an innate cellular mechanism that protects myelin-producing cells against inflammatory stress, the study authors stated.
Senior author Brian Popko, PhD, the Jack Miller Professor of Neurological Disorders at the University of Chicago, and his colleagues tested the drug on multiple mouse models of MS.
They previously showed that oligodendrocytes possess an innate mechanism that responds to stressors such as inflammation, temporarily shuts down almost all normal protein production in the cell, and selectively increases the production of protective proteins.
When the mechanism is malfunctioning or overloaded, such as by the chronic inflammation seen in MS, oligodendrocyte death and demyelination is increased significantly, the authors noted.
A recent study found that the hypertension drug guanabenz enhances this stress response pathway independent of its antihypertension actions. To test the suitability of guanabenz as a potential treatment for MS, Dr Popko and his associates exposed cultured oligodendrocyte cells to interferon gamma, resulting in greatly increased myelin loss and cell death.
Treating these cells with guanabenz prevented myelin loss and restored cell survival to near normal levels, they stated. Oligodendrocytes that were not exposed to interferon gamma were unaffected by guanabenz, suggesting that it enhances only an active stress response pathway.
When treated with guanabenz, mice that are genetically engineered to express high amounts of interferon gamma in their brains were protected against oligodendrocyte and myelin loss. Treated mice retained several times more myelination and oligodendrocytes than untreated mice.
To study a chronic model of MS, the researchers immunized mice with a component of myelin, triggering an immune response against myelin similar to MS in humans. Clinical symptoms developed, but guanabenz administered a week after immunization significantly delayed the onset of these symptoms and reduced peak severity. Treatment also prevented symptoms in about 20% of the mice.
To study the suitability of guanabenz as a therapeutic agent after MS symptoms have already appeared and peaked, the researchers used a mouse model in which symptoms relapse and remit, cycling from high severity to low severity to high again over time. They administered guanabenz immediately after symptoms peaked and found a nearly 50% reduction in severity during the next relapse cycle.
“Guanabenz appears to enhance the cell’s own protective machinery to diminish the loss of myelin, which is the major hallmark of MS,” said Dr Popko. “While there have been many efforts to stimulate re-myelination, this now represents a unique protective approach. You don’t have to repair the myelin if you don’t lose it in the first place.”
“Human MS predominantly follows a relapsing-remitting pattern,” said co-author Sharon Way, a National MS Society Postdoctoral Fellow at the University of Chicago. “Our hope is that this approach would provide protection against future relapses by making them milder and less frequent.”
The findings point to promising avenues for the development of new therapeutics against MS, the researchers concluded. “Guanabenz will probably not be a standalone drug, but we hope that it can be developed for use in combination with other medications,” Dr Popko said.
The study was reported on March 13, 2015 in Nature Communications.
• Guanabenz, a drug that is FDA-approved for high blood pressure, also prevents myelin loss and alleviates clinical symptoms of MS in mice.
• The drug appears to enhance an innate cellular mechanism that protects myelin-producing cells against inflammatory stress.
• The findings point to promising avenues for the development of new therapeutics against MS.