Researchers Identify Compounds That Might Help in Spinal Cord Repair

Contact: Charmayne Marsh 202-872-4445 in Washington

April 4--11, 2002, in Orlando407-685-8070

EMBARGOED FOR RELEASE: Monday, April 8, 4:30 p.m., Eastern Time

Researchers identify compounds that might help in spinal cord repair

ORLANDO, Fla., April 8 -- Researchers at Johns Hopkins School of Medicine have identified a set of compounds that appear to overcome an important barrier to regenerating damaged nerves. Their findings could lead to new treatments for spinal cord injury, multiple sclerosis and other neurological conditions.

Targeting a newly discovered mechanism that inhibits the growth of damaged nerves, the researchers found that these compounds caused dissected rat nerves to regenerate under controlled laboratory conditions. Findings were described today at the 223rd national meeting of the American Chemical Society, the world's largest scientific society.

The results add to a growing body of evidence that repairing spinal cord injury -- once thought impossible -- may one day occur, says Ronald L. Schnaar, Ph.D., a professor in the Department of Pharmacology at the university, located in Baltimore, Md., and lead investigator in the study.

"We are getting at the mechanisms that underlie one of the problems in nerve regrowth, but there are others," says Schnaar. "There's no one answer. There is no magic formula for spinal cord repair." Animal studies testing the nerve-regenerating chemicals began recently, he adds.

Nerves consist of axons, long extensions that carry electrical signals. Axons are wrapped by an insulation called myelin, which is essential for normal electrical conduction. When nerve cells are damaged, as in spinal cord injury, myelin sends signals that stop the axons from regenerating.

Schnaar and his colleagues found that molecules called "MAG" (myelin associated glycoprotein) on the myelin send inhibitory signals to complementary molecules called gangliosides on the surface of nerve cell axons. While the MAG-ganglioside interactions are normally stable, MAG binds to and clusters the gangliosides together during nerve injury. It is this clustering of the gangliosides on the nerve cell surface that is thought to inhibit nerve growth, they believe.

While MAG inhibition has been known for some time, Schnaar's lab is the first to identify gangliosides as the nerve cell targets for this inhibition. In the current study, the researchers focused on ways to unlock this inhibition in order to restore nerve growth.

They identified four chemicals -- including antibodies and enzymes known to interfere with myelin-axon interactions -- that induced nerve regeneration in rat brain cells under controlled laboratory conditions, according to Schnaar. He is now testing the nerve-regenerating factors in animal models with damaged nerves to determine if these therapies can work in living systems. Preliminary results are not yet available, he says.

"In the [human] body, nerve damage is much more complicated than our laboratory conditions, and this new knowledge, by itself, is unlikely to solve the problem of nerve regeneration," cautions Schnaar. "However, it is our hope that our discoveries, along with other new discoveries on the molecular basis for nerve regeneration, will help in the search for therapies to improve functional recovery after nervous system injury or disease."

About 11,000 new cases of spinal cord injury occur in this country each year. While there is no cure for paralysis, there are a number of treatment options for nervous system disease and injury, including drugs, cell transplants, artificial nerves and rehabilitation therapy.

The National Institutes of Health, the National Multiple Sclerosis Society and the Stollof Family Fund provided funding for this study.

-- Mark T. Sampson

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The paper on this research, CARB 41, will be presented at 4:25 p.m., Monday, April 8, at Convention Center, Room 314A, Level Three, during the symposium, "Multivalent Carbohydrate-Protein Interactions."

Ronald L. Schnaar, Ph.D., is a professor in the departments of pharmacology and neuroscience at the Johns Hopkins School of Medicine in Baltimore, Md.

#13184 Released 04/8/2002

Embargoed: Monday, April 8, 4:30 p.m. Eastern Time CARB 41 [497999] Crosslinking nerve cell surface gangliosides: A mechanism for regulating nerve regenerationRonald L. Schnaar, Alka A. Vyas, Gregory J. Fredericks, and Susan E. Fromholt, Department of Pharmacology, Johns Hopkins School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, Fax: 410-955-4900, [email protected], Phone: 410-955-8392

Gangliosides, the major glycoconjugates of nerve cells, are ligands for a brain lectin -- Myelin-Associated Glycoprotein. MAG is expressed on the innermost wrapping of myelin, apposed to the nerve axon, where it stabilizes myelin-axon interactions. However, MAG also inhibits axon outgrowth, limiting recovery after nerve injury. Using cerebellar neurons in vitro, we demonstrated that MAG binds to nerve cell surface gangliosides to inhibit nerve regeneration. MAG may initiate inhibition via multivalent clustering of nerve cell surface gangliosides. This hypothesis was tested using anti-ganglioside monoclonal antibodies. Addition of bivalent IgG-class anti-ganglioside antibodies had no effect on neurite outgrowth. However, when the antibodies were first pre-complexed with secondary antibodies, they mimicked MAG. This inhibitory system was successfully reconstituted in neuroblastoma cells by exogenous ganglioside addition followed by multivalent clustering. We conclude that multivalent ganglioside clustering on the nerve cell surface is an important signaling event in the control of nerve regeneration.

Embargoed: Monday, April 8, 4:30 p.m., Eastern Time

CARB 41 Non-technical Summary

* Briefly explain in lay language what you have done, why it is significant and its implications, particularly to the general public.

Nerve cells in the brain and spinal cord make partnerships with support cells which surround and nurture them, helping them function efficiently and ensuring their long-term survival. In one such partnership, the nerve cell axons - long extensions which carry electrical signals - are wrapped with insulation, called myelin, made by support cells. Myelin insulation is essential for nerve electrical conduction - its loss leads to diseases such as Multiple Sclerosis (MS) and Guillain Barre Syndrome (GBS). However, for reasons that are not altogether clear, myelin also has a dark side. When nerve axons are damaged, such as in spinal cord injury, the myelin stops them from regenerating. In large part, myelin blockade of axon regeneration is responsible for the lack of recovery from nervous system injury. It is the goal of researchers to discover how myelin stops nerves from regenerating. With that knowledge new ways to enhance recovery after nervous system injury (such as spinal cord energy) might one day be developed.

Myelin and axons communicate using a molecular "handshake" - molecules on the surface of the myelin fit snuggly with complementary shaped molecules on the axon to initiate cell-to-cell communication. We have discovered that molecules called "MAG" on myelin engage complementary molecules called "gangliosides" on the surface of the nerve cell axons. When MAG first binds to, and then clusters the gangliosides together, signals are sent into the nerve cells which blocks their regeneration. The clustering of the ganglioside on the nerve cell surface is essential for the blockade to occur.

With this knowledge we have been able to reverse this specific interaction and restore regeneration in nerve cells in Petri dishes under carefully controlled laboratory conditions. Nerve damage is very much more complex than our laboratory conditions, and this new knowledge, by itself, is unlikely to provide aid to those suffering with nerve injury. However, it is our hope that our discoveries, along with other new discoveries on the molecular basis for nerve regeneration, will help in the search for therapies to improve functional recovery after nervous system injury or disease. The knowledge also has the potential to help us understand the late-onset progressive nerve deficits in diseases such as MS.

* How new is this work and how does it differ from that of others who may be doing similar research?

This work is new and has not yet been published. There is one other laboratory (at GalaxoSmithKline) who has confirmed our results in this area. Other major laboratories around the world are discovering different molecular "handshakes" that are involved in enhancing or inhibiting nerve regeneration. It is our hope that the knowledge gained can be combined to develop new therapies.

* Indicate if the material in your presentation (or similar research) has received prior media coverage and, if so, which publications or broadcast stations might have reported it.

The work presented here has not received media attention per se. However, we received scientific media interest in earlier advances of this work after the fall, 1999 Neuroscience meetings. In particular, we were featured in an article in "Molecular Medicine Today".

* Corresponding author's name and business title or position:

* Work department:

* Business address including organization:

* Telephone:

* Fax:

* E-mail address:

Ronald L. Schnaar, ProfessorDepartments of Pharmacology and NeuroscienceThe Johns Hopkins School of Medicine725 N. Wolfe StreetBaltimore, MD 21205 USAphone: 410-955-8392; fax: 410-955-4900http://www.med.jhu.edu/schnaar

* Name and contact information for corresponding author's organization's public relations person:

Marjorie Centofanti, Asst. DirectorOffice of Public AffairsJohns Hopkins Medicine550 Bldg Suite 1100Baltimore, MD 21205(410) 955-8725 (voice)[email protected]

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