125anti-Nogo-A treatment in a rodent model of stroke (7 days after infarct) signifi cantly
decreased infarct volume in comparison to animals with no treatment [ 51 ].
Ameliorating infl ammation via Nogo-A modulation has also been observed in
TBI. In a rat model of TBI, treatment with a Nogo-A antibody signifi cantly increased
axonal sprouting while decreasing behavioral defi cits in comparison to a non-
treatment group [ 52 ]. Several groups have assessed the viability of using Nogo-A
antibodies to enhance neuroregeneration post injury in both murine and non-human
primate models of SCI injury [ 53 – 56 ]. Caroni and Schwab fi rst demonstrated the
ability to augment neurite outgrowth and axonal growth using monoclonal antibod-
ies to Nogo-A using cultured optic nerve explants [ 53 ], spurring many other groups
to investigate the effi cacy of Nogo-A antibodies. Leibscher et al. demonstrated the
effectiveness of this technique in rat models of SCI, recording that antibody treated
groups exhibited signifi cantly enhanced regeneration of corticospinal neurons [ 54 ].
Soon after, the fi rst non-human primate model of anti-Nogo-A administration was
tested on Marmoset monkeys [ 55 ]. This group reported signifi cantly enhanced
sprouting and growth of lesioned spinal cord axons into and through the lesion site
[ 55 ]. Freund et al. corroborated these fi ndings in a Macaque monkey model [ 56 ]. A
similarly promising approach for encouraging axonal growth is to target down-
stream intracellular signaling pathways such as the Rho/ROCK pathway, inhibition
of which has been shown by a number of groups to promote axonal regeneration
from neurites [ 57 ]. Rho/ROCK receptor antagonists like C3-exoenzyme, Y-27632,
and ibuprofen have been associated with improved locomotor outcome in murine
models of SCI. Several studies have found that administration of either Y-27632 or
C3 transferase to inactivate Rho was suffi cient to stimulate axon regeneration in SCI
models [ 58 – 60 ]. Other groups corroborate the use of Y-27632 both in vivo and
in vitro and also suggest that the effectiveness of treatment with Y-27632 is both
dependent on dosage and timing: acute administration of high doses being most
effective and low doses being potentially detrimental [ 60 – 63 ].
7.3 Modulation of the Infl ammatory and Immune Response
As the infl ammatory response progresses in the CNS after injury, the injury region
is fl ooded with a myriad of infl ammatory and immune response signaling factors. In
an effort to induce neuroprotective signaling within the injury microenvironment
and potentially mitigate the detrimental effects of CNS injury, molecular targets to
modulate this response have been highly researched. For the purpose of this chapter,
only a few specifi c factors will be discussed as they relate to modulating the injury
microenvironment in both the spinal cord and brain: tumor necrosis factor alpha
(TNFα), interleukin 1-β (IL-1β), vascular endothelial growth factor (VEGF), fi bro-
blast growth factor 2 (FGF-2), and brain-derived neurotrophic factor (BDNF). The
discussion will be centered on the role of various drugs/molecules, their delivery
mechanisms, and how they modulate the infl ammatory process after CNS injury.
7 Regenerative Strategies for the Central Nervous System