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TNFa (
Bai, Dergham, et al., 2010; Lebrun-Julien et al., 2010
), which may
promote the insertion of Ca-permeable AMPA receptors into RGCs,
leading to excitotoxic death (
Lebrun-Julien et al., 2009
). Inhibition of
p75 receptors in M¨ ller glia results in a neuroprotective effect of
exogenous NGF (
Bai, Shi, et al., 2010
). As another example, following
rAAV overexpression of CNTF in a transgenic mouse model of retinitis
pigmentosa, the rod a and b waves are significantly reduced despite an
increase in the survival of these photoreceptors (
Bok et al., 2002; Liang
et al., 2001
). A similar reduction of photoreceptor function is seen when
AAV-CNTF is injected into the retinas of normal rats, suggesting that
despite its beneficial effects on cell survival following injury, CNTF is
not necessarily the optimal candidate for the clinical treatment of retinal
pathologies (
Schlichtenbrede et al., 2003
).
15. CONCLUSIONS
Exogenous neurotrophic factors have a beneficial effect on the regen-
eration of adult RGC axons, not only by potentiating the effects of intrinsic
growth-promoting programs but also by counteracting at least some of the
inhibitory signaling within, as well as extrinsic to, the neuron. Some factors
such as CNTF elicit long-distance regeneration and can be applied at the
soma or in the vicinity of the regrowing axons themselves, other factors such
as BDNF or NT-4/5 elicit mostly terminal sprouting responses and are per-
haps best applied distal to an injury. Not all viable RGCs respond in the same
way to exogenous neurotrophic support, and only a proportion appear
capable of long-distance axonal regrowth in adulthood. The capacity to
regrow an axon may vary between subtypes of RGC and the site of injury,
but in addition, depending on whether factors are delivered to the eye as
bolus recombinant injections or via chronic delivery, RGCs can respond
by altering receptor configurations or by switching on genes that regulate
responses to a given factor. Indirect, non-RGC-mediated actions of
neurotrophic factors may also have complex effects on viability and axonal
responsiveness after injury. In addition, in the best of all possible worlds,
regeneration of RGC axons must eventually be associated with the reforma-
tion of appropriately mapped synaptic connections with target neurons in
the brain. Oversupply of growth-promoting factors during the period of
reinnervation may hinder such selective interactions (
Rodger, Goto, Cui,
Chen, & Harvey, 2005; Sauv´ et al., 1995; Vukovic, Plant, Ruitenberg,
& Harvey, 2007
).
