Cell Biology
Broken Hearts May
Mend After All
Neuroscience
Breathing Restored After Severe Spinal-cord Injury
Immunology
Insulin Prods Development of Type 1 Diabetes
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Overweight Undermines Health
Gene Network Discovered Supporting Cell Migration
Voracious Kudzu Drains Thirst for Alcohol
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Three HMS Professors Elected to NAS
New Appointments to Full Professor
New Members Join Academy of Arts and Sciences
Gawande to Speak on Class Day
In Memoriam
Unexpected Tragedy in a Little
Girl’s Expected Death
Breathing Restored After Severe Spinal-cord Injury
New Animal Model Shows That Common Drug Works Wonder
It has been over 2,000 years since the Greek physiologist Galen made his classic study of spinal- cord injury. Examining the wounds of gladiators and other traumatically injured patients, he found that lesions to the spinal cord followed a grim logic—the higher the damage, the greater the paralysis. The link between injury and paralysis still looms in most people’s minds. Yet when an accident occurs, moving is often one of the last things that severely injured patients and their doctors worry about. Breathing is usually the first.
Photo by Steve Gilbert
A serotonin-like drug given days or weeks after injury temporarily restored breathing in spinal cord–injured rats. “We do not know whether giving drug earlier and more frequently would cause a blossoming of neuroplasticity,” said Howard Choi (back right), shown with colleagues (from left) Deniz Konya, Yang Teng, Kimberly Newton, and Allyson King.
“After an injury, all these immediate and life-threatening symptoms start to manifest. To a patient, the immediate concern is their breathing function, bladder function, chronic pain, muscle spasticity, skin sores,” said Yang Teng, who is director of spinal cord–injury research at the West Roxbury Veterans Administration Medical Center (WRVA). “You talk with patients and some of them would say that leaving the wheelchair is last on their agenda because they want to be able to breathe without a ventilator.”
Two years ago, Teng and his colleagues found that they could temporarily restore breathing in rats with lower spinal-cord injuries by administering a common drug, buspirone. But it was unclear if the drug, which works by mimicking the effects of the neurotransmitter serotonin, could do the same in animals with higher, more devastating, spinal-cord injuries—in large part because such animal models did not exist. Howard Choi, HMS clinical fellow in physical medicine and rehabilitation, Teng, and their colleagues have developed a rat model with injuries at the fifth cervical segment, which is where most human spinal injuries occur. They have found that buspirone and another serotonin agonist restored breathing even in these more seriously injured animals. The findings appear in the May 4 Journal of Neuroscience.
Fighting for Breath
Treatments have come a long way since the time of Galen, when it was considered
a waste to give water to spinal cord–injured gladiators since they would
die anyway. Yet even today doctors rely on rather archaic methods to keep patients
breathing. When they arrive at the scene of an accident, emergency medical
technicians often intubate an injured person and provide air through a mechanically
operated airbag. Once in the emergency room, patients are put on a ventilator.
Though many spinal cord–injured patients eventually recover their breathing,
it may take weeks, months, or even years. Because they are unable to effectively
cough out respiratory secretions, patients are extremely susceptible to potentially
lethal infections during that time and often require daily physical chest manipulations.
“Medications like the one we have been investigating are very exciting because they can potentially reduce the need for maneuvers like that,” said Choi. “And if people can breathe stronger on their own, the need for ventilation may potentially be eliminated.” Buspirone has other things going for it. The FDA has approved its use for treating anxiety. It has few side effects because it works on a specific target, the serotonin 1A receptor. All this makes it a candidate for quick translation into the clinic. “We are looking into the possibility of clinical trials now that we have validated it in a clinically relevant model,” said Teng, HMS assistant professor of surgery at Children’s Hospital Boston.
In fact, he and Choi hope that their new rat model will open the door to finding other function-restoring compounds. “We desperately want to have a model that will emulate the clinical situation of chronic respiratory deficiency so we can use it to screen for drugs,” said Teng.
It is easy to see why such a model has been lacking. Keeping an animal alive, let alone functioning, after a cervical spinal-cord injury is nearly impossible. The lower spinal cord–rat model, for years the main laboratory model, was developed in the early 1900s by an American researcher. He found that by lesioning the spinal cord of dogs between the eighth and tenth thoracic vertebrae, he could produce hind-limb paralysis while letting animals stay self-sufficient. It was while working on a rat version of the model in graduate school that Teng first observed very transient breathing disorders. One of his professors had shown that morphine’s respiration-suppressing effects could be counteracted by the serotonin agonist 8-OH DPAT. Teng tried the drug, and also buspirone, on the lower thoracic–injured rats. “It restored their breathing,” he said. “But we knew that the underlying cause of loss of respiratory function in lower-thoracic injury is very different from cervical injury—different neuromuscular systems are involved. We wanted to develop a model that would accurately reflect this.”
The
50 Percent Solution
Teng and Choi thought one way to keep a cervically injured rat alive
would be to administer a contusion to just half of the spinal cord. “One
half of the body works, while the other does not,” said Choi, who
is a clinician. Delivering such a lesion turned out to be a delicate balancing
act. The spinal cord is buried deep inside the body at the neck and thorax. “You
have to perform very deep surgery to get down there,” he said. “It
takes practice to do the surgery quickly and cause minimal trauma to the
tissue while still rendering the effect you desire.”
Choi spent several months perfecting the surgical technique. Using a device developed in the 1940s for noninvasively monitoring breathing, the plethysmograph, he began his experiments. In the earlier study, Teng delivered serotonin agonist one day after injury and restored breathing in the lower thoracic–injured rats for four hours. Choi followed a similar protocol, but delivered the drug four days after injury. Sure enough, breathing was restored, and for the same length of time. What is more, the drugs restored breathing when delivered two and even four weeks after injury.
Still, the effects lasted only four hours. “This is the time frame for rats,” Choi said. “We don’t know how it would affect humans. Also, we gave the medicine at a relatively late time. We don’t know what effect it would have if we gave it immediately, and more frequently.”
The researchers plan to investigate these possibilities. There are also tantalizing theoretical questions to explore. For example, how does the drug wake up, if only briefly, the respiratory system? Serotonin is famous for its modulatory effects—that is, sensing when synapses need to be active or quiescent. “So we think the serotonin agonists may stimulate plasticity at the neuroanatomical level,” Teng said. “They may enhance neuron survival. And there is some evidence that they may activate previously silent synapses. Now that we have this model, we can start to answer these questions.”