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axonal regrowth within an autologous peripheral nerve (PN) graft sutured
onto the transected ON (
Cui et al., 2003
).
Given the convergence of growth-promoting and inhibitory signals on
the same intracellular signaling pathways, it is not surprising that combina-
torial treatments that simultaneously activate “beneficial” neurotrophin
pathways and counteract inhibitory factors have been successful. For exam-
ple, when coinjected into the eye with rCNTF but not rBDNF, analogues
that elevate cAMP increase the regeneration of RGC axons into a PN graft
sutured onto the cut ON (
Cui et al., 2003; Park, Luo, Hisheh, Harvey, &
Cui, 2004
), and addition of an agent that blocks Rho signaling enhances
regrowth in PN grafts to an even greater extent (
Hu, Cui, et al., 2007
).
This additional effect is seen because, as reviewed elsewhere (
Harvey
et al., 2006
), PN contains MAG as well as proteoglycans that can impede
axonal regeneration after injury. As another example, blockade of
epidermal growth factor receptor activation enhances the growth-
promoting actions of endogenous or exogenous neurotrophins on RGC
axons, and there is an associated repression of myelin-associated
inhibitory signaling through regulated intramembranous proteolysis of
p75/TROY receptors (
Berry, Ahmed, Douglas, & Logan, 2010
). As a
final example, antagonists of the protein LINGO-1 enhance the RGC
survival effects of injected rBDNF (
Fu et al., 2009
). Further types of
combinatorial approaches have been described and reviewed in detail
elsewhere (e.g.,
Ahmed, Berry, & Logan, 2009; Cui, Cho, So, & Yip,
2004; Fischer et al., 2004; Hu, Cui, et al., 2007; Lingor et al., 2008;
Logan et al., 2006; Tropea, Caleo, & Maffei, 2003
).
7. NEUROTROPHIC SUPPORT AND AUTOLOGOUS PN
GRAFTS
As alluded to above, autologous PN grafts containing Schwann cells
provide a bridging environment more conducive to the long-distance
regeneration of adult RGC axons (
Berry, Rees, Hall, Yiu, & Sievers, 1988;
Bray & Aguayo, 1989; Harvey et al., 2006; Heiduschka & Thanos, 2000;
Watanabe, 2010
). Using this model, it is possible not only to count the
number of regrowing RGC axons but also retrogradely label regenerating
neurons for morphological characterization and determination of the
proportion of viable RGCs that initiate a regenerative response.
Physiological analysis is also possible, and if the PN grafts are inserted into
central visual target regions then visual behavior due to regeneration and
