Researchers at the UCSD School of Medicine have identified a fibrin-
derived peptide that inhibits this specific inflammation process in
mouse models of multiple sclerosis (MS), reducing MS symptoms.

A fibrous protein called fibrinogen, found in circulating blood and
important in blood clotting, can promote multiple sclerosis when it
leaks from the blood into the brain, triggering inflammation that
leads to MS-related nerve damage. Researchers at the University of
California, San Diego (UCSD) School of Medicine have identified a
fibrin-derived peptide that inhibits this specific inflammation
process in mouse models of MS, reducing MS symptoms.

"Current strategies to develop therapies to fight MS primarily
target T cells," said Katerina Akassoglou, Ph.D., assistant
professor in UCSD's Department of Pharmacology, whose study was
published in the March 19 issue of Journal of Experimental
Medicine. "Blood proteins have been neglected as a therapeutic
target, but this research shows that a blood clotting factor is an
important player in MS."

MS is an inflammatory disease that affects the central nervous
system, causing symptoms such as loss of balance and muscle
coordination, and changes in cognitive function. The disease is
marked by loss of myelin, a material that coats nerve fibers. Past
studies showed that the destruction of the myelin sheath is
associated with the accumulation of fibrinogen deposits in the brain
of human MS patients. In this study, Akassoglou and colleagues
showed that fibrinogen is not merely associated with the damage in
MS, but an active participant. Fibrinogen activates macrophage cells
in the brain called microglia, causing inflammation which damages
myelin.

The scientists sought to design a therapeutic strategy that would
block the damaging effects of fibrinogen without affecting its
beneficial blood coagulation. Studying a mouse model, the
researchers identified a specific receptor called Mac-1 that is
expressed by microglial cells and binds to fibrinogen. Mice
expressing a mutant form of fibrinogen that failed to bind Mac-1 had
fewer inflammatory lesions and less severe MS symptoms. Blocking the
interaction between Mac-1 and fibrinogen after the first episode of
paralysis using the fibrin peptide prevented subsequent relapses. It
also prevented further microglia activation and damage to myelin in
the diseased mice, allowing them to survive with improved motor
function.

"Importantly, this approach blocks fibrin's interaction with
microglia, but not with platelets, so clotting wouldn't be
impacted," said Akassoglou, adding that this potential MS therapy
might also have applications to other blood-brain barrier diseases
where blood leakage and microglia activation is present such as
spinal cord injury, Alzheimer's disease or stroke.

Funding for the study was provided in part by the National Institute
for Neurological Disorders and Stroke, part of the National
Institutes of Health, and by the National Multiple Sclerosis Society.