Scientists Finger Surprise Culprit In Spinal Cord Injury

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.

"This is an unusual way of looking at spinal cord injury. Much of the focus of research has been on trying to re-grow portions of the spinal cord. We're trying to stop the damage up front," says Nedergaard, a professor in the Department of Neurosurgery and a researcher in the Center for Aging and Developmental Biology.

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.

Normally researchers studying spinal cord injury and conditions like Alzheimer's disease or stroke give most of their attention to neurons, which send electrical signals and make up the nerves that are vital to everything we do. But gradually scientists have warmed to the idea that astrocytes play a vital role in our health. Astrocytes fulfill a vital "housekeeping" role, nourishing neurons, supplying them with chemicals they need to do their job, and allowing them to keep their signals crisp by vacuuming up excess chemicals.

Ten years ago, Nedergaard discovered that astrocytes send signals to the neurons and the neurons respond. The latest research, funded by the National Institute of Neurological Disorders and Stroke and the New York State Spinal Cord Injury Research Program, extends the work and shows that astrocytes play a central role in our health.

"For a long time, astrocytes were thought of simply as the housekeepers of the brain, feeding the neurons and regulating their environment," says Nedergaard. "But astrocytes are much more active than we have thought. It appears that sometimes astrocytes even give out the instructions telling neurons what to do. It's very likely they play an important role in many human diseases."

The paper will appear in the August issue of Nature Medicine and was published on-line last week. Other authors from the University of Rochester include graduate student Xiaohai Wang, post-doctoral associate Takahiro Takano, researchers Qiwu Xu and Wei Guo Peng, technician Pingjia Li, and collaborator Steven Goldman. The paper also includes authors from New York Medical College, where Nedergaard worked before joining the university last year.