ReviewNeurotrophin roles in retinal ganglion cell survival: Lessons from rat glaucoma models☆
Introduction
The retinal pathology of glaucoma is characterized by selective RGC loss that is attributed to cell death by apoptosis (Quigley et al., 1995, Kerrigan et al., 1997, Quigley, 1999). The specific downstream signals and effector molecules involved in RGC apoptosis have been the subject of intense investigation and scientific review (Nickells, 1999, Nickells, 2007, Farkas and Grosskreutz, 2001, Huang et al., 2005, Libby et al., 2005), and will not be considered in detail here. However, the key upstream signals that trigger the apoptotic cascade in RGC in glaucoma are less clear and deciphering them is the main subject of this review.
Elevated IOP is the most recognized risk factor for primary open-angle glaucoma. Studies in primates demonstrate that experimentally elevated IOP results in axonal transport obstruction at the optic nerve head (Minckler et al., 1977, Minckler et al., 1978). When IOP is acutely elevated in rats, the retrograde transport of radiolabeled brain-derived neurotrophic factor (BDNF), a potent trophic factor for RGC, is obstructed (Quigley et al., 2000). Further, immunolocalization studies suggest that the BDNF receptor, TRKB, accumulates in the optic nerve head (Pease et al., 2000). These observations support the suggestion that transport obstruction inhibits the retrograde delivery of NT/TRK receptor complexes from the brain to the RGC soma, resulting in the deprivation of neurotrophic support that triggers apoptosis (Quigley, 1995, Pease et al., 2000, Quigley et al., 2000, Vrabec and Levin, 2007). An important implication of this concept is the supposition that the appropriate therapeutic manipulation of the NT signaling pathways will indefinitely prolong the survival of injured RGC. These closely related concepts are referred to as the NT hypothesis and will be examined in this review.
Section snippets
NT and RGC survival
This hypothesis is attractive because NT are known to promote neuronal survival and regeneration in many experimental paradigms. When deprived of retrograde neurotrophic support from target neurons, developing sensory and sympathetic neurons die by apoptosis (Purves, 1988, Oppenheim, 1991). The application of exogenous BDNF to the superior colliculus reduces developmental cell RGC death (Raff et al., 1993, Frade et al., 1997, Ma et al., 1998). NT have important survival properties for adult
Modeling glaucoma in laboratory rats
With these concepts in mind, experimental glaucoma models in rats have been used to explore aspects of the NT hypothesis. These models all rely on the production of elevated IOP and their characteristics and suitability have been reviewed (Danias et al., 2002, Levkovitch-Verbin, 2004, Morrison et al., 2005, Morrison et al., 2008a, Pang and Clark, 2007). While many variations in how the models are modified and implemented exist, there are basically three techniques commonly used to elevate IOP.
Endogenous NT and receptor levels
Using the hypertonic saline model and immunohistochemistry, we examined the sequence of changes in retinal and optic nerve head protein distribution that accompany exposure to elevated IOP (Johnson et al., 2000). At IOP levels approximately twice normal values for 1 week, immunostaining for BDNF and NT4/5 was reduced in the optic nerve head and the inner layers of the retina, changes that were accompanied by evidence of optic nerve axon degeneration. After longer exposures, retinas contained
Neuroprotection strategies designed to rescue injured RGC
While our knowledge of the early responses of RGC to pressure-induced injury is still very incomplete, glaucoma models have been implemented in a number of studies designed to support RGC survival during and after pressure-induced injury.
Roles for additional trophic factors in RGC survival
In addition to members of the NGF family, other trophic factors may contribute to RGC survival by signaling via AKT and/or ERK kinases. Using the cautery model to initially double IOP levels, Kanamori et al. found a slow decline to baseline IOP at about 3 months and a 35% RGC loss at 6 months (Kanamori et al., 2004). They examined retinal immunostaining patterns for total and activated forms of AKT in flat-mounted retinas during that time course. Labeling for activated AKT was absent in the
Conclusions
The NT hypothesis is, perhaps, the most widely recognized theory proposed to explain RGC loss due to elevated IOP and, importantly, it incorporates axonal injury at the optic nerve head as a key component. The currently available rat glaucoma models offer the opportunity to examine this hypothesis in a paradigm in which only the risk factor of IOP is altered. As summarized in this review, recent studies of NT signaling using these in vivo models have encompassed both the endogenous responses of
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Supported by NIH grants EY010145, EY016866 and an unrestricted grant from Research to Prevent Blindness, Inc.