March 25, 2004
Two Approaches For Preventing Injured Nerve Cell Death

When an accident or any other event damages nerve cells much of the nerve cell death and resulting disability occurs hours or even days after the traumatic event. The injured nerves, many of which are not damaged in ways that make death inevitable, go through changes that cause them to commit cell suicide. Two approaches for how to prevent nerve cell death have just been reported. The first approach, tried at Wake Forest University, involves use of so-called heat stress proteins which normally are found inside of cells but which if delivered outside of cells still prevent a substantial fraction of damaged nerve cells from dying.

WINSTON-SALEM, N.C. – New findings in animals suggest a potential treatment to minimize disability after spinal cord and other nervous system injuries, say neuroscientists from Wake Forest University Baptist Medical Center.

“Our approach is based on a natural mechanism cells have for protecting themselves, called the stress protein response,” said Michael Tytell, Ph.D., a neuroscientist and the study’s lead researcher. “We believe it has potential for preventing some of the disability that occurs as a result of nervous system trauma and disease.”

The research showed that up to 50 percent of the motor and sensory nerve cell death could be prevented in mice with sciatic nerve injury. It is reported in the current issue of Cell Stress and Chaperones, a journal of stress biology and medicine.

“We are on our way to developing a treatment that is effective in preventing motor nerve cell death, which is significant to people because loss of motor neurons means paralysis,” said Tytell, professor of neurobiology and anatomy at Wake Forest Baptist.

The goal of the work is to prevent or minimize the “secondary” cell death that occurs in the hours and days after a spinal cord or brain injury. During this period, cells surrounding the injury can become inflamed and die, a cascading response that worsens disability.

Either these proteins could be delivered at injury sites or drugs could be developed to stimulate the production of Hsc70 and Hsp70 in damaged nerve cells.

For the study, the researchers treated injured sciatic nerves in mice with Hsc70 and Hsp70. In mice treated with the proteins, cell death was reduced by up to 50 percent compared to mice that weren’t treated.

Tytell said it is a novel idea that cells can be successfully treated with a protein that is ordinarily made inside the cells.

“We don’t know whether the protein is functioning in the same way as when it’s made in the cells,” he said. “We’re working to learn more about this effect. If we can understand it better, we’ll know what form it should be in and what the doses should be to maximize the protective benefits.”

Tytell and colleagues hope to use their knowledge about the proteins and how they work to develop drugs that could be used to treat injury. One idea is to develop a drug that would increase the production of the protective proteins.

Another group which includes lead author Sung Ok Yoon of Ohio State University used an antibody to neutralize a protein released by damaged nerve cells that plays a role in causing cell death.

Researchers report in the current online issue of the Proceedings of the National Academy of Sciences that they were able to prevent the death of damaged neurons by neutralizing a specific protein the injured cells secreted. Neurons carry messages from the brain to the spinal cord and the rest of the body.

Damaged neurons are rendered useless by the physical interaction of two cellular proteins – proNGF and p75, the researchers report. They learned that treating these injured cells with a proNGF antibody kept the proteins from interacting. In turn the neurons were saved from almost certain loss.

The approach of using an antibody to neutralize proNGF (which is a precursor to Nerve Growth Factor) saved most of the cells that otherwise would have died.

The researchers saw substantial increases in proNGF and p75 in damaged neurons within 24 hours after injury. Levels of p75 peaked three days after injury, as did neuronal death.

The researchers took another group of damaged neurons and treated these cells with an antibody to proNGF. Doing so kept proNGF from interacting with p75, and resulted in a 92 percent survival rate of otherwise damaged neurons.

"The antibody notably reduced the number of neurons that normally die after such injury," Yoon said. "But it's too soon to say if these rescued cells would function normally again after treatment.

"We do know that injury decreased the number of healthy, viable neurons by half," she said. "But the number of intact neurons remained at nearly 100 percent after antibody treatment."

To treat cancer what we need are better ways to cause cell death and to prevent cells from dividing. To develop stem cell therapies we need better ways to order cells to move to desired target locations, to divide, and to become specialized for various purposes. But for nerve cell damage caused by trauma or perhaps by toxins what we need is the ability to prevent the series of steps that lead cells to commit suicide (caled apoptosis). That two different teams have almost simultaneously come up with two different approaches for doing this in lab settings is encouraging. These results are not going to immediately lead to new treatments but they do demonstrate that such treatments are probably possible to create and these results provide useful information about what directions to pursue for further research.

Share |      Randall Parker, 2004 March 25 02:12 AM  Biotech Therapies

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