Biology Reference
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reformation of retinofugal connections can be assessed (e.g.,
Sauv
´
,Sawai,&
Rasminsky, 1995; Thanos, 1992; Vidal-Sanz, Aviles-Trigueros, Whiteley,
Sauv´, & Lund, 2002
). In adult cats, intravitreal injection of BDNF,
CNTF, and forskolin increases RGC viability and axonal regeneration into
PN grafts, especially RGCs of a particular physiological subtype, the beta
cells, and most usually the ON responsive subtype (
Watanabe, 2010
).
Intravitreal injections of neurotrophic factors, when combined with PN
grafts, also provide intriguing and important information about how the site
of axotomy relative to the parent cell body influences long-distance regen-
erative ability. RGC degeneration occurs more rapidly the closer the ON is
cut to the back of the eye; however, in the presence of a PN graft, RGC
loss—as a proportion of the initial population—is similar in central
and peripheral retina (
Hu, Cui, et al., 2007
). After intravitreal injections
of rCNTF, combined with either a cell-permeant analogue of cAMP,
8-(4-chlorophenylthio)-adenosine-3
0
,5
0
- cyclic monophosphate (CPT-
cAMP), and/or a Rho GTPase inhibitor (C3-11), there was enhanced
survival of peripheral RGCs, yet the proportion of viable RGCs that
regenerated an axon into a PN graft was two to three times higher when
RGCs were located close to the optic disk (
Hu, Arulpragasam, et al.,
2007
). Centrally located RGCs are, of course, closer to the PN graft, but
this central-to-peripheral regeneration gradient was seen even though the
intravitreal CNTF injections enhanced RGC viability across the entire ret-
ina. A distinction between factors that promote neuronal survival versus ax-
onal regeneration has been noted previously (
Goldberg & Barres, 2000;
Leaver, Cui, Bernard, & Harvey, 2006
).
8. NONVIRAL DELIVERY SYSTEMS FOR
NEUROTROPHIC FACTORS
As discussed earlier, bolus injections of relatively high, almost certainly
nonphysiological, concentrations of neurotrophic factors into the eye may
not necessarily be the optimal approach for eliciting maximal regeneration
of RGC axons because of compensatory responses in RGCs and other ret-
inal cells. In addition, it is expensive to give repeat injections of recombinant
growth factors, and the injections themselves will initiate inflammatory and
other changes in the eye (
Cao et al., 2001
). Methods that permit more
long-term expression of neurotrophic factors are therefore under investiga-
tion. As reviewed elsewhere (
Andrieu-Soler et al., 2006; Harvey et al., 2006;
Hellstr¨m & Harvey, 2011
), more sustained delivery may result from
