Chicago: An FDA-approved drug for high blood pressure, guanabenz, prevents
myelin loss and alleviates clinical symptoms of multiple sclerosis (MS)
in animal models, according to a new study. The drug appears to enhance
an innate cellular mechanism that protects myelin-producing cells
against inflammatory stress. These findings point to promising avenues
for the development of new therapeutics against MS, report scientists
from the University of Chicago in Nature Communications on Mar. 13.
"Guanabenz appears to enhance the cell's own protective machinery to
diminish the loss of myelin, which is the major hallmark of MS," said
senior study author Brian Popko, PhD, Jack Miller Professor of
Neurological Disorders at the University of Chicago "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."
Multiple sclerosis is characterized by an abnormal immune response
that leads to inflammation in the brain and the destruction of myelin --
a fatty sheath that protects and insulates nerve fibers. MS is thought
to affect more than 2.3 million people worldwide and has no known cure.
Popko and his colleagues have previously shown that oligodendrocytes,
the brain cells which produce myelin, possess an innate mechanism that
responds to stressors such as inflammation. It temporarily shuts down
almost all normal protein production in the cell and selectively
increases the production of protective proteins. When this mechanism is
malfunctioning or overloaded -- by the chronic inflammation seen in MS,
for example -- oligodendrocyte death and demyelination is significantly
increased.
A recent study found evidence that guanabenz, a drug approved for
oral administration for hypertension, enhances this stress response
pathway independent of its anti-hypertension actions. To test the
suitability of guanabenz as a potential treatment for MS, Popko and his
team exposed cultured oligodendrocyte cells to interferon gamma -- a
molecule that increases inflammation -- 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. Oligodendrocytes that were
not exposed to interferon gamma were unaffected by guanabenz,
suggesting that it enhances only an active stress response pathway.
The team then tested the drug on multiple mouse models of MS. 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
around 20 percent of mice from developing symptoms at all.
To study the suitability of guanabenz as a therapeutic 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 percent
reduction in severity during the next relapse cycle.
"Human MS predominantly follows a relapsing-remitting pattern," said
co-author Sharon Way, PhD, 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 team confirmed that guanabenz acts by temporarily blocking the
reactivation of a protein known as eukaryotic translation initiation
factor 2 (eIF2α). When deactivated, eIF2α initiates the stress response
pathway. Blocking its reactivation results in a prolonged stress
response and provides protection against cell death. The researchers
hypothesize that guanabenz stimulates a protective cascade -- because
fewer oligodendrocytes die, less immune cells are recruited to the
brain, which results in a decreased inflammatory response and
preservation of myelin levels.
The team notes that eIF2α becomes reactivated after a certain amount
of time through pathways that guanabenz does not act upon, so eventually
the stress response mechanism will shut down regardless of treatment.
However, the protective efficacy of guanabenz and its ability to
alleviate relapses, coupled with its established safety profile, makes
for promising clinical implications.
The Myelin Repair Foundation, which funded this work as part of a
multi-institutional effort to accelerate research and development of
treatments for MS, has entered into a cooperative agreement with the
National Institutes of Health to assess guanabenz as a therapeutic
candidate in MS clinical studies.
"Guanabenz will probably not be a standalone drug, but we hope that
it can be developed for use in combination with other medications,"
Popko said. "Some current treatments can have severe side effects -- for
example dangerous infections in the brain. It would be of tremendous
benefit for patients to have effective, less-risky therapies.
The study, "Pharmaceutical integrated stress response enhancement
protects oligodendrocytes and provides a potential multiple sclerosis
therapeutic," was also supported by the National Institutes of Health.
Investigators at Northwestern University, Case Western Reserve
University and the Myelin Repair Foundation assisted in these efforts.
Additional authors include Joseph R. Podojil, Benjamin L. Clayton, Anita
Zaremba, Tassie L. Collins, Rejani B. Kunjamma, Andrew P. Robinson,
Pedro Brugarolas, Robert H. Miller and Stephen D. Miller.