Healthcare and Medicine Reference
In-Depth Information
( cont'd )
BOX 1
glial cells support neurite outgrowth, adult astrocytes and
oligodendrocytes appear to inhibit neurite outgrowth.
When a central nerve bundle is injured in a mammal, the
axons are usually unable to regrow across the wound and
thereby reestablish connections they had lost. Part of the
problem, it appears, is the invasion of the wound site with
various glia, which produce repulsive cues that the axons
cannot navigate around. By X-irradiating mouse spinal
cords during neonatal development, it was possible to
create mice that are deficient in glial cells. In these
animals, spinal axons regenerated past a transection
point, a behavior that they never display in normal
animals (Schwab and Bartholdi, 1996).
To find the molecular components involved in inhibit-
ing central regeneration, the system was brought into
culture where it was found that CNS neurons stop, and
sometimes collapse, when they touch oligodendrocytes.
Liposomes from these cells and preparations of myelin
were used to identify an inhibitory factor that causes CNS
growth cones to collapse. A monoclonal antibody to this
factor, which is now called Nogo, was then made and
tested in culture for its ability to block the collapsing activ-
ity. In the presence of antibody, axons grew over oligo-
dendrocytes without stopping or collapsing. The antibody
was then tested in vivo, using mice with partially severed
spinal cords. In the presence of Nogo antibodies, many
more axons were able to regenerate beyond the crush than
in control animals, and there was considerable functional
recovery suggesting that Nogo is a critical component of
the failure of spinal regeneration (Schnell and Schwab,
1990; Bregman et al., 1995), although there has been some
debate as to whether knocking out Nogo in mice leads to
enhanced regeneration. The Nogo receptor was identified
and found to be a receptor for other myelin-derived
inhibitory factors such as Myelin Associate Glycoprotein
(MAG), indicating that this receptor may provide an
insight into where the signals that inhibit regeneration
converge (Fournier et al., 2001).
Astrocytes often accumulate around CNS wounds,
forming complex scars. These cells produce an extracel-
lular matrix that is inhibitory to axon regeneration, and
one of the key components of this inhibitory material may
be chondroitin sulfate glycosaminoglycan chains found
on many proteoglycans in the astroglial scar (Asher et al.,
2001). Even when plated on the growth-promoting ECM
component, laminin, spinal neurons stop growing when
they confront a stripe of chondroitin sulfate. In culture,
the inhibitory component can be digested away with
chondroitinase, rendering the matrix more permissive to
axon growth and regeneration. To see if chondroitinase
could be used to treat models of CNS injury in vivo, rats
whose spinal cords had been transected, were treated
locally with the enzyme. Such treatment restored synap-
tic activity below the lesion after electrical stimulation of
corticospinal neurons and promoted functional recovery
of locomotor activity (Bradbury et al., 2002).
It is clear that progress is being made on the extrinsic
factors that inhibit axon regeneration, but there is still the
problem that older central axons simply do not regener-
ate very well even when the conditions are good. Adult
axons can grow for a short distance (<500 mm) in many
central locations (Liu and Chambers, 1958; Raisman and
Field, 1973). The growth of very young neurons does not
appear to be so restricted in an adult nervous system.
Human neuroblasts are able to form long axon pathways
when transplanted into excitotoxin-lesioned adult rat
striatum (Wictorin et al., 1990). Similarly, mouse embry-
onic retinal ganglion cells are able to grow long distances
within the rostral midbrain of neonatal rats and selec-
tively innervate some normal targets (Radel et al., 1990).
Indeed, myelin inhibits regeneration from old but not
young neurons. What do these young axons have that
older axons do not? It was found that the levels of cAMP
in young growth cones are much higher than in older
axons (Cai et al., 2001). By increasing the cAMP levels, one
can turn old neurons into neurons that behave more like
young ones in terms of their regenerative potential (Qiu
et al., 2002). Moreover, the recovery from spinal injury in
neonatal rats is markedly reduced by lowering cAMP
levels.
Another key intrinsic difference between old and
young axons may have to do with protein synthesis. Young
growth cones are full of protein synthetic machinery, but
the axons of older neurons do with less of such machinery.
There appears to be a good correlation between the ability
of a growth cone to make new proteins and its ability to
regenerate in vitro. The challenge now will be to find ways
to crank up the protein synthetic machinery in the growth
cones of damaged CNS neurons to see if this can aid recov-
ery. When considering all these data, it seems that full
recovery after an injury may require a strategy for dealing
with both intrinsic and extrinsic factors.
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