UCSD researchers determine fibrin depletion decreases multiple sclerosis symp

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Tissue damage due to Multiple Sclerosis (MS) is reduced and lifespan

lengthened in mouse models of the disease when a naturally occurring

fibrous protein called fibrin is depleted from the body, according

to researchers at the University of California, San Diego (UCSD)

School of Medicine.

The study, reported online the week of April 19, 2004 in the

Proceedings of the National Academy of Sciences, identifies fibrin

as a potential target for therapeutic intervention in the disease,

which affects an estimated one million people worldwide.

However, the research team cautions that fibrin plays an important

role in blood clotting and systemic fibrin depletion could have

adverse effects in a chronic disease such as MS. Therefore,

additional research is needed to specifically target fibrin in the

nervous system, without affecting its ability as a blood clotting

protein.

" Multiple sclerosis is a nervous system disease with vascular

damage, resulting from the leakage of blood proteins, including

fibrin, into the brain, " said the study's first author, Katerina

Akassoglous, Ph.D., a UCSD School of Medicine assistant professor of

pharmacology. " Our study shows that fibrin facilitates the

initiation of the inflammatory response in the nervous system and

contributes to nerve tissue damage in an animal model of the

disease. "

MS is an autoimmune disease that affects the central nervous system

(CNS), causing a variety of symptoms including loss of balance and

muscle coordination, changes in cognitive function, slurred speech,

bladder and bowel dysfunction, pain, and diminished vision. While

the exact cause of MS is unknown, a hallmark of the disease is the

loss of a material called myelin that coats nerve fibers, and the

inability of the body's natural processes to repair the damage.

Although fibrin is best known for its important role in blood

clotting, recent studies have shown that fibrin accumulates in the

damaged nerves of MS patients, followed by a break down of myelin.

However, the cellular mechanisms of fibrin action in the central

nervous system have not been known, nor have scientists determined

if fibrin depletion could alleviate or lessen the symptoms of MS.

In work performed at The Rockefeller University, New York and the

UCSD School of Medicine, in collaboration with colleagues at the

University of Vienna, Austria and Hellenic Pasteur Institute,

Greece, researchers studied normal mice and transgenic mice with an

MS-like condition. The normal mice had normal spinal cords and with

no fibrin deposits in the central nervous system. In contrast, the

transgenic mice showed fibrin accumulation, inflammation and a

degradation of the myelin in their spinal cord. When transgenic mice

were bred without fibrin, they developed a later onset of the MS-

like paralysis as compared to their transgenic brothers that had

fibrin. In addition, the fibrin-depleted mice lived for one

additional week longer than the normal, disease-impacted mice. This

difference is significant in animal models such as mice that have

very short lifespans.

Fibrin's role in excessive inflammation was shown in a follow-up

experiment where transgenic mice were shown to experience high

expression of pro-inflammatory molecules, followed by myelin loss,

as compared to the fibrin-negative transgenic mice with no signs of

inflammation or myelin destruction.

In addition to the genetic deletion of fibrin, the researchers

tested drug-induced fibrin depletion, which was accomplished by

administering ancrod, a snake venom protein, to the transgenic mice.

Consistent with the genetics-based experiments, the pharmacological

depletion also delayed the onset of inflammatory myelin destruction

and down-regulated the immune response. Previous studies by other

investigators who used ancrod in experimental autoimmune

encephalomyelitis (EAE), another animal model of MS, also showed

amelioration of neurologic symptoms.

In the current study, the investigators also used cell culture

studies to determine that fibrin activates macrophages, the major

cell type that contributes to inflammatory myelin destruction.

Akassoglou said that " further research to identify the cellular and

molecular mechanisms that fibrin utilizes in the nervous system will

provide pharmacologic targets that will specifically block the

actions of fibrin in nervous system disease. "

The study was funded by grants from the National Institutes of

Health, the Wadsworth Foundation Award, and the National Multiple

Sclerosis Society.

Sidney Strickland, Ph.D., Laboratory of Neurobiology and Genetics,

The Rockefeller University, New York, in whose lab Akassoglou first

began her studies, was the senior author of the paper. Additional

authors were , Ph.D., UCSD Department of Pharmacology; Jan

Bauer, Ph.D. and Hans Lassmann, M.D., Laboratory of Experimental

Neuropathology, University of Vienna, Austria; Lesley Probert,

Ph.D., and Vivi Tseveleki, B.Sc., Laboratory of Molecular Genetics,

Hellenic Pasteur Institute, Athens, Greece; and Mercado,

B.Sc., The Rockefeller University