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Researchers Discover Factor That Kills Cells After Brain Injury

Infusion of Antibody for 7 Days Dramatically Boosts Nerve Cell Survival After Brain Injury

New York, NY and Dallas, TX (Mar 19, 2004)

Dead and dying nerve cells directly affected by stroke, other injury, or neurodegenerative diseases like Alzheimer's are known to trigger cell death, or apoptosis, in their healthy neighbors. This cell death cascade is often more devastating than the original injury in terms of brain and spinal cord damage. But new evidence in an animal model suggests that these neurons could be saved.

Researchers from Weill Cornell Medical College, University of Texas Southwestern Medical Center, Ohio State University, and University of Saarland (Germany) report in the current online issue of Proceedings of the National Academy of Sciences (PNAS) that they were able to prevent the injury-induced death of cortical neurons in mice and rats by neutralizing a specific protein called proNGF that cells in the injured brain secrete.

The researchers used an antibody to proNGF to prevent its interaction with another protein called p75 that is found on the surface of injured neurons, saving them from almost certain loss. This treatment boosted nerve cell survival to over 90% in injured rats compared with a 61-66% cell survival seen in rats not treated with the antibody.

While the antibody infusion used in the study is not appropriate for treatment of humans, the experiment published in PNAS validates proNGF as a viable target for discovering molecules that can be used to block proNGF in patients. ProNGF is an unprocessed form of a nerve cell-protecting substance called NGF, or nerve growth factor. The study validated this target not only by showing that blocking proNGF prevents neuronal death, but by demonstrating that proNGF and the p75 receptor with which it interacts are upregulated after injury.

I think the implications of this are quite exciting, said Dr. Barbara Hempstead, the O. Wayne Isom Professor of Cardiovascular Medicine at Weill Cornell Medical College. ProNGF is a molecule that is made in response to injury, when it is secreted by cells, and can be found outside the cell in the cerebrospinal fluid. P75 is a receptor that neurons upregulate following injury. This experiment indicates that if you give antibodies that block the binding of proNGF's to p75, you can prevent the death of neurons, at least in animal models.

If you could identify a compound that could pass the blood-brain barrier and impair the binding of proneurotrophin to cell receptors, then it could be a potential drug that could be tested in animals and eventually patients, she said. The blood-brain barrier is a protective layer of cells that stops most compounds from entering the central nervous system a problem that has to be overcome when finding drugs to treat brain conditions.

In the study, the researchers looked at injuries to the corticospinal tract, nerves that carry signals from the brain to motor nerves, which carry out movement. They are frequently damaged in strokes. Past studies have found that after such an injury, about 40% of corticospinal nerve cells die within 14 days.

Dr. Klaus Giehl, who started this work at the University of Saarland in Homburg, Germany, and completed it at the the University of Texas Southwestern Medical Center at Dallas, led the study using a rigorous model of corticospinal injury in rats that he has developed.

Dr. Sung Ok Yoon of Ohio State University, a corresponding author of the paper, provided important biochemical experiments to document that proNGF binds to p75 in vivo, and that proNGF can be detected in the cerebral spinal fluid of animals following brain injury. She has previously identified proNGF as an important apoptotic factor following brain injury in rodent models.

Additional authors of the study are A. Harrington, B. Leiner, C. Blechschmitt, J. Arevalo, R. Lee, K. Moerl, and M. Meyer.

The work was funded by grants from Deutsche Forschungsgemeinschaft (Drs. Giehl and Meyer); NIH (Drs. Hempstead and Yoon); ACS (Dr. Yoon); the German-Israeli Foundation (Dr. Meyer); and the Max-Planck Institute of Neurobiology (Drs. Meyer and Moerl).

This prestigious paper follows quickly on another for Dr. Hempstead: a recent issue of Nature featured a study by Dr. Hempstead and a different set of collaborators, who demonstrated that another protein called sortilin is also required for the proNGF/p75 signaling system to kill neurons. Dr. Hempstead's initial discovery that proNGF is the preferred ligand for p75 was published in Science in 2001.

Cornell University has filed for patent protection on these findings and is actively seeking partners to develop new medicines based on the findings.2453084pubkebloom&&16:20-11- 5-2004kebloom12:09- 8-18-200403_19b_04

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