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and clear evidence that inactivation of either Rho or ROCK is sufficient to
promote long-distance axon regeneration in the injured CNS.
2.2. Inactivation of Rho and neuroprotection
Both neurons and glia undergo apoptosis after SCI in rat, which leads to the
formation of a large lesion cavity. Recent data show that activation of Rho
after SCI contributes to the cell death in neurotrauma. It has been well docu-
mented that after SCI, injured cells upregulate the expression of p75NTR, a
neurotrophin receptor and also a coreceptor for NgR1 (
Barker, 2004;
Casha, Yu, & Fehlings, 2001
). p75NTR also is known for a role in
inducing apoptosis in some cell types when it is upregulated. The NgR1/
p75NTR complex signals to Rho, and the role of this complex in cell
death is not well understood. There is possible involvement of Rho
signaling to PTEN because PTEN controls the phosphorylation and
activation of the survival kinase Akt and ERK1/2 (
Kilic et al., 2010
).
Inactivation of Rho with cell-permeable C3 or with Cethrin is neuro-
protective in both rat and mouse SCI models (
Dubreuil et al., 2006, 2003;
Lord-Fontaine et al., 2008
) as well as in traumatic brain injury and stroke
models (
Dubreuil et al., 2006; Laufs et al., 2000
). A single application of
cell-permeable C3 has a durable effect on Rho inactivation for at least
1 week (
Dubreuil et al., 2003
), and it would be interesting to follow this
time course further. In the SCI experiments, TUNEL-labeled cells
correlated with the cells expressing high levels of active Rho, and the
overall extent of tissue loss was reduced after treatment with Cethrin
(
Dergham et al., 2002; Lord-Fontaine et al., 2008
). In addition to studies
of SCI, two independent studies show that either cell-permeable C3 or
transfection of neurons with C3 is neuroprotective for RGCs after
cutting the optic nerve (
Bertrand et al., 2005; Fischer et al., 2004
). There
is also evidence that ROCK inhibition is neuroprotective in culture or
after optic nerve injury (
Hirata et al., 2008; Lingor et al., 2008
).
Together, replication by independent laboratories shows that inactivation
of Rho or ROCK after CNS injury protects cells from apoptosis. These
findings are important because neuroprotective treatments after SCI have
the potential to lead to improved functional recovery.
2.3. Inactivation of Rho and functional recovery after SCI
Independent verification of functional recovery after SCI has been a very
controversial field lately. To determine the treatments with the most poten-
tial to be translated to clinical study, the National Institute of Neurological
