Neurotrophin roles in retinal ganglion cell survival: Lessons from rat glaucoma models

Abstract

The neurotrophin (NT) hypothesis proposes that the obstruction of retrograde transport at the optic nerve head results in the deprivation of neurotrophic support to retinal ganglion cells (RGC) leading to apoptotic cell death in glaucoma. An important corollary to this concept is the implication that appropriate enhancement of neurotrophic support will prolong the survival of injured RGC indefinitely. This hypothesis is, perhaps, the most widely recognized theory to explain RGC loss resulting from exposure of the eye to elevated intraocular pressure (IOP). Recent studies of NT signaling using rat glaucoma models, have examined the endogenous responses of the retina to pressure exposure as well as studies designed to augment NT signaling in order to rescue RGC from apoptosis following pressure-induced injury. The examination of these studies in this review reveals a number of consistent observations and provides direction for further investigations of this hypothesis.

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.