August 06, 2004
Key Reason Found For Paralysis After Spinal Cord Injury

Some types of spinal cord injury do not result in an immediate severing of the spinal cord and yet paralysis does eventually develop hours after the injury. A group of University of Rochester Medical Center researchers have pinpointed the reason for the neuronal cell death that produces paralysis: astrocyte support cells around a spinal injury respond to the injury by releasing ATP that signals to the neurons to kill themselves.

ATP, the vital energy source that keeps our body’s cells alive, runs amok at the site of a spinal cord injury, pouring into the area around the wound and killing the cells that normally allow us to move, scientists report in the cover story of the August issue of Nature Medicine.

The finding that ATP is a culprit in causing the devastating damage of spinal cord injury is unexpected. Doctors have known that initial trauma to the spinal cord is exacerbated by a cascade of molecular events over the first few hours that permanently worsen the paralysis for patients. But the finding that high levels of ATP kill healthy cells in nearby regions of the spinal cord that were otherwise uninjured is surprising and marks one of the first times that high levels of ATP have been identified as a cause of injury in the body.

The team found that excess ATP damages motor neurons, the cells that allow us to move and whose deaths in the spinal cord result in paralysis. Even more noteworthy was what happened when the research team from the University of Rochester Medical Center blocked ATP’s effects on neurons: Rats with damaged spinal cords recovered most of their function, walking and running and climbing nearly as well as healthy rats.

While the work opens up a promising new avenue of study, the work is years away from possible application in patients, cautions Maiken Nedergaard, M.D., Ph.D., the researcher who led the study. In addition, the research offers promise mainly to people who have just suffered a spinal cord injury, not for patients whose injury is more than a day old. Just as clot-busting agents can help patients who have had a stroke or heart attack who get to an emergency room within a few hours, so a compound that could stem the damage from ATP might help patients who have had a spinal cord injury and are treated immediately.

“There is no good acute treatment now for patients who have a spinal cord injury,” says Nedergaard. “We’re hoping that this work will lead to therapy that could decrease the extent of the secondary damage.

Anyone know how this team at Rochester blocked ATP's effects?

Neuronal support cells known as astrocytes release ATP that binds to the P2X7 receptor on neurons in such large concentraitions that the neurons interpret the binding as a signal to kill themselves in a cell suicide process known as apoptosis.

The findings come courtesy of the same technology that underlies the firefly’s mating habits. The firefly uses the enzyme luciferase to convert ATP to the glow it uses to light up and attract mates. Nedergaard’s team used the same enzyme to study the levels of ATP around the site of spinal cord injury, recording a very a bright signal for several hours around the site of injury.

While low levels of ATP normally provide a quick and primitive way for cells to communicate, Nedergaard says, levels found in the spinal cord were hundreds of times higher than normal. The glut of ATP over-stimulates neurons and causes them to die from metabolic stress.

Neurons in the spinal cord are so susceptible to ATP because of a molecule known as “the death receptor.” Scientists know that the receptor, also called P2X7, also plays a role in regulating the deaths of immune cells such as macrophages, but its appearance in the spinal cord was a surprise. ATP uses the receptor to latch onto neurons and send them the flood of signals that cause their deaths. Nedergaard’s team discovered that P2X7 is carried in abundance by neurons in the spinal cord.

The source of the ATP that kills the neurons provided another revelation for researchers. Star-shaped cells known as astrocytes, long considered simply as passive support cells for neurons in the nervous system, produce the high levels of ATP.

This discovery opens up several avenues of attack for the development of treatments. First of all, a method might be found to create a chemical environment around the astrocytes that looks like no injury has occurred. The astrocytes would not react to the injury because the chemical changes caused by the trauma effectively would be hidden from them. Another possibility would be a drug that would bind somewhere in astrocytes to suppress ATP release even though the astrocytes are getting external signals typical of trauma. At the intermediate point between ATP release and ATP binding methods of getting rid of the ATP might be employed. For instance, a drug that would catalyze the breakdown of ATP would eliminate the ATP after it was released by the astrocytes. Another possibility would be a drug that would compete with ATP to bind at the P2X7 site. Such a drug would need to be able to bind at the site while not triggering the receptor to change shape the way ATP does when ATP binds at the site. A fourth target area would be within the neurons. A cascade of events within neurons is set off by ATP binding to P2X7. It might be possible to find drugs that will interrupt that cascade at any number of stages to prevent cell death.

Discoveries that point in a clear direction for where to intervene in a disease process do not get as much attention as do actual treatments. Yet the identification of high quality targets for intervention greatly speed up the development of treatments. This discovery of the importance of ATP and the P2X7 receptor is probably going to lead to the development of a number of treatments that will prevent paralysis after many spinal cord injuries and other types of nerve injuries.

Share |      Randall Parker, 2004 August 06 02:13 PM  Biotech Therapies

Grady said at August 13, 2004 9:09 AM:

The OxATP(oxidized ATP) they mention in the paper blocks binding of ATP to the P2X7 receptor. Another compound, PPADS works similarly, but reversibly.

These compounds are known inhibitors of purinergic receptors. See here.

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