Saturday, May 14, 2005

Breathing Easier After Spinal Cord Injuries

Common tranquilizer may save lives

Injuries to the upper spinal cord can take a victim's breath away.

Most people don't know that breathing difficulties are the leading cause of disease and death after such injuries. Indeed, respiratory failure causes more deaths than limb paralysis does, and survivors often become dependent on ventilation machines.

For the first time, Harvard researchers successfully tested an inexpensive, readily available class of drugs that has restored normalcy to rats who suffered the same loss of breath as humans who receive spinal cord injuries in combat, falls, car wrecks, or by gun or knife. These drugs include buspirone, a tranquilizer used to ease anxiety in the elderly and to help people quit smoking.

"This is the first experiment to demonstrate the complete recovery of respiratory function in conscious rats with injuries in the cervical [upper] region of the spinal cord," says Yang "Ted" Teng, assistant professor of surgery at Harvard Medical School and director of spinal cord injury research at the Veterans Administration Boston Healthcare System. "In light of their availability, we believe drugs such as buspirone offer a novel strategy for treating post-spinal-cord-injury respiratory dysfunction. Also, our work will allow further investigation of other promising drug therapies for this highly morbid and sometimes fatal complication."

Teng also believes that further exploration of the restorative action of drugs, along with use of neural stem cells, could lead to new treatment for breathing complications that arise from other disorders like stroke and Lou Gehrig's disease, also known as amyotrophic lateral sclerosis (ALS).

Breathing easy

Teng and his team dealt specifically with injuries in the cervical region, the upper part of the spinal cord in the neck area, where damage produces the most serious types of breathing problems. An injury in this area left actor Christopher Reeve a quadriplegic and put him on a ventilator.

Most affected is the phrenic nerve that carries impulses to and from the diaphragm. Attached to the spine, the diaphragm muscles draw air into the lungs and push carbon dioxide out. When these nerves don't operate properly, breathing becomes shallow and rapid. The lack of oxygen can also lead to cramps, chest pains, dizziness, confusion, unconsciousness, and, sometimes, death.

Teng worked closely with Howard Choi, a postdoctoral fellow and a physician. They wanted to develop a nonsurgical way to restore function in the damaged nerves. With the help of colleagues from Harvard-affiliated research hospitals, Teng and Choi looked at a group of buspirone-like drugs recently shown to counteract breathing problems produced by lack of oxygen, morphine overdose, and sleep apnea. In the latter, respiratory nerve problems lead to temporary stoppage of breathing, a suffocating experience that prevents a good night's sleep at best and is life threatening at worst. The drugs relieved this condition, providing "a nice hint that they may work in spinal cord injuries," says Teng.

A few years ago, Teng and some colleagues from Georgetown University in Washington, D.C., tried the drugs on rats with injuries in the thoracic part of the spine, below the cervical sections. They worked successfully, but spinal cord injuries to the thoracic segments are far less frequent that those of the cervical segments.

Teng, Choi, and their collaborators designed an experiment with rats that would simulate as far as possible profound human breathing dysfunction. After carefully measuring the normal breathing of the animals, then surgically injuring them, the drugs were injected into their abdomens.

The experimental results were announced in the May 4 issue of the Journal of Neuroscience by the team, which includes researchers from Children's Hospital Boston, Brigham and Women's Hospital, Spaulding Rehabilitation Hospital, and the Veterans Administration Boston Healthcare System. "The majority of the animals recovered to their pre-injury states," Teng sums up the report. "They can breathe without help and feed themselves. Some of them did not receive the injections until two weeks after their injury, and their breathing was restored to normal. That's very encouraging."

Humans are next

To the obvious question of when these drugs will be tested in humans, Teng answers, "as soon as possible. Some of the drugs, like buspirone, have already been approved for other uses and are readily available. So we've begun planning and seeking funds for humans trials."

Two of the questions to be answered by such tests are the proper dosages, which probably won't be the same as for reducing anxiety or apnea, and whether or not people tolerate the dosages as well as rats do.

Previously, Teng led another team that used an antibiotic called minocycline to restore movements in rats paralyzed by thoracic spine damage. In such traumas, tissues continue to discharge toxic chemicals that may kill and disable nerves for days and weeks after the original injury. The hind limbs of rats that didn't receive the drug remained paralyzed while those that did were able to stand on their hind legs and to walk again.

"We would like to do experiments that combine the two drug types," Teng says. Minocycline might provide immediate protection of endangered nerves, while the buspirone-type medications would stimulate function in the spared nerves. These combinations, he points out, may be effective in a wide variety of diseases that affect movement including strokes, Lou Gehrig's disease, multiple sclerosis, cerebral palsy, and Parkinson's.

Teng and his colleagues also see a potential for such combinations in emergency situations where protection and stimulation of nerve function could be started in a matter of minutes. Combat medics in Iraq or Afghanistan, or emergency medical technicians in Boston or Los Angeles might be trained to begin such treatments before the secondary damage becomes disabling or lethal.

What about reversing paralyses, giving paraplegics and quadriplegics the ability to use their arms and legs again? "In these cases, you are not just protecting nerves from further damage or restoring their function, you must reconstitute them, rebuild them," Teng explains. That might be possible someday with the aid of neural stem cells, which can, with the help of growth factors and other emerging tools, regenerate nerves that have been destroyed.

"That task is daunting; it's the ultimate challenge."

By William J. Cromie - Harvard News Office