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Two hundred Mississippians suffer a spinal cord injury (SCI) each year, one of the highest rates in the United States. For survivors who join the 300,000 other Americans living with chronic SCI, effective pain management and return of motor function have been elusive.
“We researchers kept coming up snake-eyes,” said Dr. Ray Grill, associate professor of neurobiology and anatomical sciences at the University of Mississippi Medical Center, who studies SCI and other neurological injuries.
Now, the odds may be in Grill's favor. He recently received a Department of Defense grant to study a two-drug therapy to battle chemotherapeutic resistance and neuropathic pain in SCI.
Chemotherapeutic resistance means that the body builds up a defense against drug treatments, decreasing a treatment's effect over time. The phenomenon occurs in some cancer treatments, but Grill and his colleagues saw something similar in SCI.
“So, why have so many drug trials failed in the search for SCI treatments?” Grill asked.
Spinal blood vessels (blue) are surrounded by cells that maintain the blood-spinal cord barrier (green) and help restore myelin after trauma (red).
One culprit is P-glycoprotein (Pgp). The protein pump limits passage of blood-born molecules across the blood-spinal cord barrier to prevent infection and damage, but also removes many drug treatments.
Grill's group found that an early inflammatory response triggered by SCI caused a dramatic increase in Pgp expression: first at the injury site, then throughout the spinal cord. The increased Pgp limited the cord's access to riluzole, a drug undergoing a clinical trial for SCI rehabilitation.
The study also suggested that spinal cord Pgp was elevated from soon after injury to as long as ten months post-injury in a rat model, paralleling the two phases of SCI: acute and chronic.
Further studies suggest that SCI may increase Pgp not only in the spinal cord but also in tissues throughout the body, including the gastrointestinal tract, the main route for oral drug absorption.
“The injury-induced expression of chemotherapeutic resistance blunts the access of treatment into the injured spinal cord or potentially into the body itself,” Grill said.
Part of the difficulty in treating SCI is the system's complexity, says Dr. Lique Coolen, professor of physiology and biophysics.
“The spinal cord is a multi-faceted system that is involved in controlling many other systems,” Coolen said. This makes understanding, let alone treating, injuries challenging.
“You must understand how something normally works in order to prevent injury and restore function,” she said.
Coolen studies a reflex generator (a bundle of nerves) in the lower spine of male rats involved in sexual function. When the generator is damaged they can become aroused, but fail to ejaculate.
Coolen's recent work is on how to potentially treat the injuries to the generator by activating certain receptors in the spinal cord. She is also interested in neuroplasticity: how the nervous system may rewire itself and adapt after damage.
However, Coolen says there are many unanswered questions, including why injuries far away from the generator - higher up the back, for example - can still disable the generator.
Coolen says that 85 to 90 percent of men with a spinal cord injury have sexual dysfunction and that it's often the top rehabilitation goal for younger patients. For other patients, goals may vary depending on the type and level of injury.
The thoracic dorsal root ganglion (a cluster of nerve cells in the spinal cord) is the first area where neuropathic pain occurs after SCI. Different types of neurons sensitive to pain can be seen using specific markers (red, green and blue).
In Grill's study, one goal is to find treatments that restore motor function and limit neuropathic pain. Patients with incomplete injuries (those that do not sever the spinal cord) may experience chronic hypersensitivity to heat or touch that does not respond well to typical pain medications. Another goal is neuroprotection: shielding nerves from further damage.
Grill will test a two-drug treatment. Rats with bruised spinal cords will take licofelone, a drug which prevents the Pgp increase and knocks out two inflammatory pathways, not one like typical anti-inflammatory drugs. They will also take riluzole, an FDA-approved neuroprotective drug used to delay nerve damage in amyotrophic lateral sclerosis patients.
If effective, then the rats' hind legs should have a wider range of motion and decreased nerve hypersensitivity. Grill also expects increased riluzole bioavailability in the spinal cord and higher uptake in the gastrointestinal tract, because Pgp expression in both systems should be turned off.
“If clinical trials for riluzole work, then it has huge implications for patients,” said Dr. Robert McGuire, professor of orthopedic surgery, who has operated on spines since 1984.
McGuire says that the first priority when a patient has fractured vertebrae is to conduct a thorough physical examination to determine extent of an injury, then stabilize the bones before sending the person to surgery or rehabilitation. Each movement could lead to a secondary spinal cord injury. The sooner a patient can stabilized, the better the outcomes.
McGuire has been involved with clinical research efforts including the development of instruments and techniques that take pressure off the spinal cord to prevent secondary injuries.
“Patients used to wear plaster casts and stay in bed for months,” McGuire said. “Then came rods, hooks and wires to stabilize the spine while the bones heal.”
Now surgeons like McGuire use small metal cages and plates to protect the cord from further damage. But while the initial operation on a patient lasts only a few hours, that person then has a lifetime of rehabilitation ahead.
“A team approach to rehab is important. Physical therapists, occupational therapists, social workers and psychologists are all involved in this process,” McGuire said. “It's best to have many people looking out for you and your best interests.”
This team also includes researchers who determine how the spinal cord works and how to treat its injuries. Grill hopes his work will breathe second life into once-unsuccessful therapies.
“If we can increase the efficacy of previously-tried drugs, that's fertile ground for research,” Grill said.
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