By EurekAlert
Thursday, November 19, 2009
WEST LAFAYETTE, Ind. - Researchers have shown how an
experimental drug might restore the function of nerves damaged in
spinal cord injuries by preventing short circuits caused when tiny
"potassium channels" in the fibers are exposed.
The chemical compound also might be developed as a treatment for
multiple sclerosis.
Because nerves usually are not severed in a common type of
spinal cord trauma, called "compression" injuries, the drug offers
hope as a possible treatment, said Riyi Shi, a professor in Purdue
University's Department of Basic Medical Sciences, School of
Veterinary Medicine, Center for Paralysis Research and Weldon
School of Biomedical Engineering.
"Compression is responsible for most spinal cord injuries,
including many resulting in paralysis," Shi said. "Since the nerves
are not severed, this type of drug represents a potential golden
opportunity to treat spinal cord injuries."
The experimental compound, 4-aminopyridine-3-methyl hydroxide,
has been shown to restore function to damaged axons, slender fibers
that extend from nerve cells and transmit electrical impulses in
the spinal cord.
Findings, based on experiments with guinea pig spinal cord
tissue, appeared online Wednesday (Nov. 18) in the Journal of
Neurophysiology. The work was led by Department of Basic
Medical Sciences doctoral student Wenjing Sun.
Shi said the findings were made possible by the
interdisciplinary nature of the work, which also involves
researchers Richard Borgens, director of Purdue's Center for
Paralysis Research and the Mari Hulman George Professor of
Neurology in the School of Veterinary Medicine; Stephen Byrn, the
Charles B. Jordan Professor of Medicinal Chemistry, and Daniel
Smith, a research assistant professor, both in the Department of
Industrial and Physical Pharmacy; and Ji-Xin Cheng, an associate
professor in the Weldon School of Biomedical Engineering and
Department of Chemistry.
The researchers subjected spinal cord tissue to stresses that
mimic what happens in a compression injury, which stretches nerves.
Then they treated the damaged axons with 4-aminopyridine-3-methyl
hydroxide.
The compound is a derivative of the drug 4-aminopyridine, used
primarily as a research tool and also to manage symptoms of
multiple sclerosis.
The axons of each nerve are sheathed in a thick insulating lipid
layer, called myelin, which enables the transmission of signals
without short circuiting, much like the insulation surrounding
electrical wires. Spinal cord trauma damages the myelin sheath,
exposing "fast potassium channels" that are embedded in the axons
and are critical for transmitting nerve impulses.
The researchers confirmed previous circumstantial evidence
suggesting injury causes the myelin insulation to recede, exposing
the channels and impairing signal transmission. Laboratory and
imaging techniques revealed the exposed channels in damaged
axons.
The researchers also discovered that 4-aminopyridine-3-methyl
hydroxide is a "potassium channel blocker," using a sophistic
laboratory technique called "patch clamp" to measure signal
conduction. Findings confirmed that the compound prevents the
exposed channels from leaking electrical current and enhances nerve
conduction in segments of the damaged spinal cord.
The compound could make it possible to sidestep spinal cord
damage by enabling axons to transmit signals as though they were
still sheathed in myelin, Shi said.
Nerves transmit signals through a series of rapid electrical
pulses, or "action potentials." For proper nerve function, the time
gap between pulses must be as brief as possible. However,
4-aminopyridine has been shown to lengthen the gap, or "refractory
period," between pulses. The researchers found that
4-aminopyridine-3-methyl hydroxide restores function without
affecting the refractory period. As a result, the damaged nerves
perform more like healthy nerves than those treated with other
drugs, he said.
Another key advantage of the new compound is that it's about 10
times more potent than 4-aminopyridine, meaning lower doses can be
used to reduce the likelihood of serious side effects.
Because myelin also is damaged in multiple sclerosis, the same
drug might be used to restore nerve function in people stricken
with the disease, Shi said. Since the newer drug can be used in
lower doses, it might be more effective than 4-aminopyridine in
treating multiple sclerosis, which affects more than 350,000 people
in the United States and 2 million worldwide, he said.
SOURCE