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injury (
Fig. 1.1
). Eye injections were made 3, 10, and 17 days after the optic
tract transection: 3 and 10 days, both 1.5
m
l injections (1:1 0.75
m
g/
m
l
CNTF, 0.05 mM CPT-cAMP); 17 days, 3
m
l injection (1:1 0.75
m
g/
m
l
rCNTF, 0.2 mM CPT-cAMP). Control-lesioned animals received intra-
vitreal saline injections at these time points. Surviving RGC numbers
assessed using
b
-III tubulin immunohistochemistry (
Cui et al., 2003
)in
sham (
n
9) animals were
not significantly different from each other, yet the volume of innervated
postlesion SC and the density of CTB-labeled axons were significantly
higher in the neurotrophic factor treated group (
Fig. 1.1
: ANOVA repeated
measures,
p
¼
6) versus rCNTF-CPT plus CPT-cAMP (
n
¼
0.037 effect of treatment). Thus, application of neurotrophic
support at the cell body can be therapeutic for distal injuries as well.
¼
14. INDIRECT ACTIONS OF NEUROTROPHIC FACTORS
Up to this point, we havemostly focused on the actions of exogenously
applied neurotrophic factors that aremediated by cognate receptors expressed
by the injured RGCs themselves. However, this is an oversimplification:
there is considerable evidence that intraocular trophic factor injections acti-
vate other cellular constituents in the eye which in turn produce factors that
may indirectly contribute to RGC survival and axonal regeneration (e.g.,
Berry et al., 2008; Cui, Yin, & Benowitz, 2009
). For example, CNTF
delivered
to the eye as a recombinant protein or via gene therapy induces a
sustained upregulation of endogenous cytokines such as CNTF and LIF,
probably expressed by M
¨
ller glia (
Leibinger et al., 2009; Muller, Hauk, &
Fischer, 2007; Park et al., 2009
). In addition, there is evidence that the
calcium-binding protein oncomodulin, expressed by blood-borne cells, is
also an important mediator of the positive effect of recombinant cytokines
and/or injury-induced inflammation on RGC viability and axonal
regeneration after ON crush (e.g.,
Benowitz & Popovich, 2011; Cui et al.,
2009; Yin et al., 2003
).
However, via complex downstream, multicellular events, the application
of neurotrophic factors can also elicit adverse off-target effects in retinal
tissue. M
¨
ller glia express a range of neurotrophic factors (e.g., LIF, pigment
epithelium-derived growth factor, BDNF, FGF2, and CNTF;
Chun et al.,
2000; Ju et al., 2000; Valter et al., 2005
) and pro-NGF expression in
particular is increased following ON axotomy (
Lebrun-Julien, Morquette,
Douillette, Saragovi, & Di Polo, 2009
). NGF (either the pro- or mature
form) binds to p75 expressed on M¨ ller cells, triggering the release of
