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recombinant factors, viral vectors, cell transplantation, as well as combinatorial
treatments involving other pharmacotherapeutic agents. Indirect, off-target effects of
neurotrophic factors on RGC axonal regeneration are also considered. There remain
unresolved issues relating to optimal delivery of neurotrophic factors, and we empha-
size the need to develop safe, reliable methods for the regulation of exogenous supply
of these factors to the injured CNS.
1. INTRODUCTION
The adult central nervous system (CNS) normally has only a limited
ability to regenerate axons after injury. There appear to be many reasons for
this, including a lack of sufficient trophic support and presence of extrinsic
inhibitory factors that limit plasticity, as well as intrinsic changes in neuronal
responsiveness that negatively impact regenerative potential. Although direct
injury to the optic nerve (ON) in humans is not common, over the past
30 years or so the mammalian retinal ganglion cell (RGC) has been a
consistent target of experimenters attempting to understand how best to
promote the viability and regenerative capacity of adult neurons after
CNS trauma (
Benowitz & Yin, 2008; Berry, Ahmed, Lorber, Douglas, &
Logan, 2008; Chierzi & Fawcett, 2001; Harvey et al., 2006
). The retina
and ON are embryologically part of the CNS, and RGCs are useful
model neurons because they can be directly targeted by injections into
the vitreal chamber and the ON is a white matter tract containing
oligodendroglia that is accessible and relatively easy to manipulate, either
by crush, stretch, or full or partial transection injury. Further, RGC
survival and axonal regrowth can readily be quantified, and the
connectivity and topographic order of regenerating RGC axons can be
assessed using anatomical, physiological, and behavioral methods. RGC
axons can also be targeted more centrally, at sites further away from the
eye, by performing intracranial ON injuries or by lesioning the optic
tract, usually between the thalamus and superior colliculus (SC). In this
way, regenerative potential of RGCs can be compared
in vivo
after
proximal versus distal axonal injuries.
The brief given to us for this review was a focus on neurotrophic factors
and axonal regeneration. We will discuss a range of diffusible peptides with
trophic actions on RGCs, including the classic neurotrophins such as brain-
derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5),
