Effects of optic nerve injury, glaucoma, and neuroprotection on the survival, structure, and function of ganglion cells in the mammalian retina

Abstract

Glaucoma is an optic neuropathy that originates with pressure-induced damage to the optic nerve. This results in the retrograde degeneration of ganglion cells in the retina, and a progressive loss of vision. Over the past several years, a number of studies have described the structural and functional changes that characterize ganglion cell degeneration in the glaucomatous eye, and following optic nerve injury. In addition, a variety of different strategies for providing neuroprotection to the injured retina have been proposed. Many of these are based on the use of brain-derived neurotrophic factor (BDNF), a particularly potent neuroprotectant in the mammalian eye and the basis of our research in this area. Of particular importance is the fact that BDNF not only promotes ganglion cell survival following damage to the optic nerve, but also helps to preserve the structural integrity of the surviving neurons, which in turn results in enhanced visual function. The studies presented here describe these attributes, and serve as the foundation for ongoing work that suggests a need to think beyond the eye in the development of future treatment strategies.

Inhibition of Histone Deacetylases 1 and 3 Protects Injured Retinal Ganglion Cells

“…[13][14][15][16] Kinetic analysis has shown that Thy-1 mRNA and proteins are gradually lost over the first 2 weeks following optic nerve crush. 17 RGC death follows around 1 to 2 weeks after Thy-1 loss.…”

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

“…We raise the hypothesis that ocular hypertension acts as an upstream activator of p38 MAPK; this may contribute to induce retinal dysfunction and degeneration. BDNF has been demonstrated to be a potent growth factor that is beneficial in neurodegenerative diseases with synaptic dysfunction [29], in RGC functions following optic nerve injury and diseases [10,11] and in murine models of glaucoma [18,19]. We should take into account the possibility that BDNF reduces retinal dysfunction in DBA/2J mice with elevated IOP [19] by attenuating p38 MAPK phosphorylation, similarly to what was previously reported for amyloid toxicity [29].…”

“…BDNF is a neurotrophic factor indispensable for the survival and plasticity of several subtypes of neurons in the nervous system, including RGC [9][10][11]. BDNF is locally produced by cells in the ganglion cell and inner nuclear layers [12]; its TrkB receptor is expressed in RGCs, amacrine and Müller cells [13] that represent the cellular target of BDNF trophic action.…”

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

“…The neurotrophins BDNF, NGF, and neurotrophin 4 (NT-4) have neuroprotective effects on retinal ganglion cells compromised by experimentally induced glaucoma or intraorbital optic nerve crush (Parrilla-Reverter et al 2009 ;Colafrancesco et al 2011 ); reviewed in Johnson et al ( 2009 ) andWeber et al ( 2008 ). BDNF and NT-4 preferentially bind TrkB, whereas NGF preferentially binds the related receptor, TrkA, and as mentioned above, LINGO-1 is co-expressed with TrkB, whereas TrkA-mediated signaling stimulates the expression of LINGO-1 Fu et al 2009 ;Skaper 2012a ).…”