Current research into the methods of
treating spinal cord injuries is focused in two areas. The first
involves primary intervention strategies to reduce nerve degeneration
that promptly follows injury. The other involves finding treatments
that will promote nerve regeneration and reconnection of the spinal
cord across the lesion (2). Whereas
sensory axons in mature humans can regenerate following injury,
axons in the central nervous system cannot (24).
In order for normal functions to return following a spinal cord
injury, the axons must survive, regrow, reconnect with their target
cells, and follow the paths of normal development. There are three
reasons why this does not happen in the adult central nervous system:
neurons die, axons do not have the ability to initiate or maintain
growth, and the environment of the injured area is not conducive
to regeneration (5, 23).
The inability of the central nervous system to allow cell regrowth
is due to the presence of inhibitory signals and the lack of growth
promoting signals. These signals can come from cells, extracellular
matrix, or other molecules that diffuse into the injury. Myelin
is one substance that greatly contributes to the axons inability
to regrow (5). Whereas myelin does
not prevent axonal regrowth in young neurons and in the peripheral
nervous system, it prevents axonal regrowth in the adult central
nervous system. Neurons lose the ability to regrow because of two
factors: the development of myelin, and the axonal response (inability
to regrow) associated with it. During spinal cord injury both the
axon and the myelin surrounding the axon are damaged. Axonal regeneration
is prevented due to its exposure to substances secreted from myelin
and the inhibitory substances related to the myelin membrane. After
the glial scar forms, axons completely lose the ability to cross
the lesion and reconnect with target cells.
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of the spinal cord in an adult rat: The dark cavern shows
the syrinx that forms a few weeks after injuriy. Here it has
prohibited the corticospinal tract (white fibers), which normally
control motor function, from regenerating.
Scientists have discovered two approaches
that could allow the neuron to regenerate and reconnect with its
target cells. The first involves trying to prompt the neuron into
a "young" state in which it would not be inhibited by the environment
of the adult central nervous system. A study by Neuman and Woolf
showed that neurons having axons in both the peripheral and central
nervous system have the ability to regrow following a lesion in
the central nervous system if a lesion was produced one or two weeks
before in the peripheral nervous system. The theory behind this
is that the peripheral nervous system conditioned the central nervous
system so that it would no longer be affected by the inhibitors
in the environment following injury (11).
In their experiment the injured fibers either grew through the lesion
or they traveled around the lesion. They showed, however, that regrowth
after complete lesion of the dorsal cord can take place in the inhibitory
environment that results from the injury. They attribute this enhanced
regenerative ability to increased growth capacity (11).
The second approach to regeneration
and reconnection involves obstructing the myelin related substances
that prevent neuron regeneration (5).
Nogo and myelin-associated glycoprotein (MAG) are two molecules
shown to inhibit axonal regeneration. When growing axons are exposed
to Nogo their growth cone breaks down. The Schwab laboratory demonstrated
that IN-1, a monoclonal antibody against CNS myelin, enhanced axonal
regrowth both on a culture of myelin and also in vivo (11).
When IN-1 secreting cells were transplanted at the same time that
the lesion was created, many axons grew rather long distances and
in some cases regained its function (11).
While the transplantation induced the long-distance growth of some
axons, 90-95% of axons showed no growth at all. This indicates that
there are inhibitors in addition to Nogo that prevent axons from
regrowing. MAG is another powerful growth inhibiting molecule. It
prevents axonal regeneration in vivo, and it is probable that any
release of MAG from myelin at the injury site contributes to the
axons inability to regrow (11). It
is likely that in addition to Nogo and MAG, there are other myelin
associated growth inhibitors (5,11).
In tests where an animals own immune system was induced to make
antibodies against all myelin associated molecules, the extent of
regrowth was greater than when specific antibodies were used, but
the regrowth was still restricted suggesting that other factors
contribute to the prevention of regeneration (5).
It is also probable that effects of these substances are not additive,
but that the presence of one is enough to prevent regeneration.
The best approach in devising ways to aid axonal regrowth is to
inhibit the effects of all of the substances simultaneously (11).
S. Keirstead, Ph.D.
growth cone: when axon growth cones are exposed to Nogo, their
growth cone breaks down.
One approach to blocking all myelin
related inhibitors was tested by Huang et al. They 'vaccinated'
mice against myelin inhibitors three weeks before injury to induce
the production of antibodies against the inhibitors. Three weeks
after injury 50% of the immunized mice showed considerable axonal
regrowth, while the control immunized group showed no regrowth (11).
As compared to the studied performed by Schwab and colleagues using
IN-1 injections, myelin-immunized mice regrew more axons and the
distance of regrowth was up to two-thirds of the spinal cord compared
to one-forth. One major question concerning myelin injection is
whether or not the antibodies have to be present along the entire
path while the axon regrows, or if their initial presence and their
presence across the lesion and through myelin inhibitors is enough
to allow regrowth. Work performed by Silver's group, indicates that
antibodies are needed only across the lesion site where the inhibitors
are present. As Davies and colleagues demonstrated in 1997, undamaged
myelin is permissive to axonal regrowth. It is therefore possible
that if the antibodies were present where the axon encounters the
myelin inhibitors, the axon could transverse the lesion and continue
its growth outside the myelin.
The glial scar also creates anther barrier
to axonal regrowth. Whereas axons are able to regrow if they do
not come in contact with damaged myelin, axonal growth ceases when
it reaches the glial scar. Although it is not known exactly what
molecules impede regrowth, some possible molecules include: developmental
growth cone inhibitory guidance cues, such as semaphorin 3A and
EphB3; extracellular matrix molecules such as the proteoglycans
versican, brevican, phosphacan, and neurocan, and some adhesion
molecules such as tenascin-R (5).
One possible approach to aid axon regeneration
is the transplantation of peripheral nerves and Schwann cells (19,
24). Schwann cells are the glial cells
in the peripheral nervous system that foster nerve regeneration
In addition to supplying guidance tubes for regenerating peripheral
axons, they produce cell-adhesion molecules, and molecules of extracellular
matrix (19). They also produce many
neurotrophic factors, which improve nerve regeneration by guaranteeing
survival, providing growth cues, and encouraging cells to produce
substances needed for growth (5). Implantation
of Schwann cells aids in axonal regeneration by supporting and guiding
the growing axon and giving them neurotrophic support. They link
each side of the lesion with living cells thus guiding the axons
during regeneration (24). They may
even foster axonal sprouting. Martin et al showed that the best
time for Schwann cell implantation is immediately following the
cord lesion because this improves cell survival and reduces the
scar tissue (19, 24).
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studying the effects of implantation of cells from the peripheral
nervous system (PNS), rats receive the implantation at the
T8 level of the spinal cord
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dorsal view of a laboratory rat with an incision (A) for cell
implantation. 2. the removal of a 5mm segment of the rats
spinal cord (B) (enlarged view of the spinal cord) 3. the
addition of peripheral nerves (C) as well as acidic fibroblast
growth factor (aFGF), and a fibrin 'glue' mixture (E) into
the gap in the spinal cord. 4. the enlargement of the PNS
graft shows the alignment (D) of the PNS cells with the gray
matter in the lower spinal cord stump.
Neurons in the olfactory mucosa are
the only neurons that are born after birth and that continue to
divide throughout adult life (19).
Olfactory ensheathing cells are specialized glial cells of the olfactory
mucosa that maintain axonal growth from the mucosa to the olfactory
bulbs. Like Schwann cells, olfactory ensheathing cells continue
to divide throughout life, but unlike Schwann cells, which are confined
to the peripheral nervous system, olfactory ensheathing cells can
enter the central nervous system by guiding olfactory axons to their
target destinations in the olfactory glomeruli. They are the only
glial cells known to be able to travel across the boundary between
the peripheral and the central nervous system (10).
Ramón- Cueto and colleagues recently demonstrated that implantation
of olfactory ensheathing cells after complete spinal cord transection
could restore both structure and function to the injured animal.
Their study, in which adult rats with complete spinal cord transection
received transplantations of olfactory ensheathing cells, showed
the greatest amount of recovery as compared to other transplantation
studies using Schwann cells, astrocytes, microglia, macrophages,
and fibroblasts. The transplantation of olfactory ensheathing cells
resulted in the recovery of proprioception
and light touch, the ability to support body weight, voluntary hind
limb movement, plantar paw placement, as
well as the long-distance regeneration of motor axons through the
transection site (28). Transplantation
of olfactory ensheathing cells could be an advantageous repair strategy
for humans because the cells can be obtained from and possibly transplanted
from adult donors (28).
Most of the current research surrounding
spinal cord regeneration deals with the best methods to improve
axon growth. Although axon regrowth is important, it alone will
not lead to functional recovery. The essentials for functional recovery
include recognition of and reconnection to targets, reenervation
of neurons and their pathways, and the recovery of functional synapses