In tests on rats, researchers at Johns Hopkins and the
University of Michigan have developed a treatment that
helps spinal cord nerves regrow after injury.
The study, whose findings were published in the July
18 issue of the Proceedings of the National Academy of
Sciences, has implications for treating people who may
face amputation of an arm after a violent injury in which
nerves are wrenched from the spinal cord. The new treatment
currently is under study for other types of traumatic
spinal cord injury.
The researchers treated experimental nerve injuries in
rats with an enzyme called sialidase that they isolated
from bacteria. Four weeks later, more than twice as many
nerves in the spinal cords of sialidase-treated rats grew
new nerve fibers compared to untreated rats.
The experimental injury in rats mimicked an injury in
humans that may occur during childbirth or in a motorcycle
accident when an arm is pulled violently away from the
body. This injury causes nerves to be yanked out of the
spinal cord. Without these nerves, the arm loses feeling
and muscle tone. Without muscle tone, the body cannot
support the weight of the arm, and many health problems can
develop.
While surgeons can sometimes reattach the nerves to
the spinal cord, this treatment is not as effective as
physicians or patients would like, in part because nerves
in the brain and spinal cord, unlike those in the rest of
the body, fail to grow new nerve fibers. Nerves in the
brain and spinal cord are surrounded by signals from other
cells in the injured area that stop them from growing.
"Molecules in the environment of the injured spinal
cord are specifically instructing the nerve end not to
regrow," said the study's director,
Ronald
Schnaar, professor of
pharmacology and
neuroscience in the Institute of Basic Biomedical
Sciences at Johns Hopkins.
"The brain and spinal cord are extremely crowded with
nerves and nerve fibers, which may be why we have developed
careful controls that tell cells to stop making new
connections," he said. "The crowded central nervous system
has ways to say 'OK, we're done' to keep nerves from
sprouting willy-nilly and making inappropriate connections.
But in gaining the ability to crowd nerves close together,
we have given up flexibility — the ability to heal
after injury.
"If you sever your finger, it can be surgically
reattached, and nerve fibers typically grow back so that
you can use your finger again," Schnaar said. "In contrast,
the injured brain and spinal cord are rocky terrain for
nerve fiber growth. Finding ways to smooth that road might
help the nerve fibers to regrow."
Several molecules in the spinal cord are known to stop
nerve fibers from growing. Schnaar refers to these
molecules as axon regeneration inhibitors, or simply
ARIs.
"Treatments that eliminate ARIs might allow the nerve
ends to regain their natural regenerative abilities as they
do in the periphery and improve recovery," Schnaar said.
The researchers looked at the boundary between the
spinal cord and the periphery to see if they could coax a
nerve end to grow out of the inhibitory spinal cord into a
more permissive environment that contains fewer ARIs. They
chose to mimic the injury commonly seen in motorcycle
accidents, called brachial plexus avulsion, because it
involves nerves at the boundary between the spinal cord and
periphery.
In anesthetized rats, the researchers surgically
severed nerves that normally extend from the spinal cord to
the shoulder. They then transplanted a nerve from the hind
leg of the same animal into the spinal cord to reconnect
the injured nerve ends.
To coax the injured nerve ends to grow fibers and
connect to the transplanted nerve, they implanted a pump to
bathe the area with one of three enzymes known to destroy
ARIs. Four weeks after transplantation and enzyme
treatment, the researchers injected dyes into the nerves to
see whether and how many nerve fibers had grown from the
injured cells of the spinal cord into the transplanted
nerve.
Rats treated with sialidase, one of the three enzymes
tested, showed well over twice the number of new nerve
fibers than rats treated with saline, which is not expected
to enhance nerve growth. Moreover, the researchers saw that
the new fibers were made by nerve cells residing in the
spinal cord.
"We have established that the enzyme sialidase, which
destroys one of the molecules that inhibits nerve
regeneration, is sufficient to robustly improve nerve fiber
outgrowth from the spinal cord," Schnaar said.
Surgical transplantation of a peripheral nerve to help
nerve fiber growth from the spinal cord has shown limited
success in humans. Lynda Yang, the study's lead author and
an assistant professor of neurosurgery at the University of
Michigan, said, "The addition of a new treatment to enhance
our current surgical management of brachial plexus avulsion
in people would be welcomed by patients and surgeons
alike." Yang helped pioneer the study of ARIs in the 1990s
while a doctoral student with Schnaar at Johns Hopkins.
Having shown in this study that sialidase can increase
the number of spinal cord nerve cells that extend fibers
into a transplanted nerve, Yang now is testing to see if
the nerves re-establish muscle control. "We're very
interested in seeing how much function you can get back,"
she said.
According to Schnaar, there is some evidence that this
transplant technique coupled with sialidase treatment can
coax other, nearby nerve cells within the spinal cord to
grow out as well. "Once you rewire, then the brain does an
amazing job of sorting it all out," he said.
Having established the ability of sialidase to improve
spinal nerve regeneration into transplanted peripheral
nerves, Schnaar and his research team at Johns Hopkins are
testing the same treatment to see whether it will help
nerve regeneration in other types of spinal cord
injuries.
"Even a small improvement might mean a lot," Schnaar
said. "People with spinal cord injuries generally are not
looking to play football but to regain basic functions. A
modest improvement in nerve regeneration might make a big
improvement in a patient's quality of life."
The researchers were funded by two branches of the
National Institutes of Health: the National Institute of
Neurological Disorders and Stroke and the National Heart,
Lung and Blood Institute; and by the Department of
Neurosurgery at the University of Michigan.
In addition to Yang and Schnaar, authors on the paper
are Ileana Lorenzini, Katarina Vajn, Andrea Mountney and
Lawrence Schramm, all of Johns Hopkins.
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