Targets of Neuroprotection in Glaucoma

Abstract

Progressive neurodegeneration of the optic nerve and the loss of retinal ganglion cells is a hallmark of glaucoma, the leading cause of irreversible blindness worldwide, with primary open-angle glaucoma (POAG) being the most frequent form of glaucoma in the Western world. While some genetic mutations have been identified for some glaucomas, those associated with POAG are limited and for most POAG patients, the etiology is still unclear. Unfortunately, treatment of this neurodegenerative disease and other retinal degenerative diseases is lacking. For POAG, most of the treatments focus on reducing aqueous humor formation, enhancing uveoscleral or conventional outflow, or lowering intraocular pressure through surgical means. These efforts, in some cases, do not always lead to a prevention of vision loss and therefore other strategies are needed to reduce or reverse the progressive neurodegeneration. In this review, we will highlight some of the ocular pharmacological approaches that are being tested to reduce neurodegeneration and provide some form of neuroprotection.

Keywords: drug targets; glaucoma; neuroprotection.

FIG. 1.

Potential targets for neuroprotection in glaucoma. There are multiple targets for neuroprotection based upon currently understood cellular mechanisms of cell death of RGCs. A number of agents target GPCRs. An important key second messenger contributing to cell death is intracellular calcium (Ca²⁺)_i. Sigma receptors (σ-1) act by attenuating calcium uptake from ionotropic glutamate receptor (NMDA receptor). In addition, sigma receptor agonists could prevent formation of the permeability transition pore by sustaining the transmembrane potential of the inner mitochondrial membrane. This would prevent the release of cytochrome c from the mitochondria. Excessive ROS cause oxidative stress, which mediates RGC apoptosis through caspase-dependent and caspase-independent pathways. Application of antioxidative strategies might be an effective approach. Sigma receptors could also associate with voltage-dependent calcium channels and diminish calcium uptake from the extracellular milieu. Endothelin receptors antagonists could act on the Gq-coupled endothelin A receptor, blocking its ability to activate phospholipase C, and thereby prevent calcium release from the endoplasmic reticulum stores. Neurotrophins act through Trk receptors (which are receptor tyrosine kinases) and promote cell survival effects by activating the MAP kinase cascade, ultimately influencing gene expression in the nucleus through transcription factors such as Elk-1. TNF-α through its receptors can also trigger apoptotic signaling resulting in cell death. Targeting TNF-R is another protective target that would prevent cell death. The use of multiple agents could synergistically act to generate robust neuroprotection of RGCs. BNDF, brain-derived neurotrophic factor; GPCRs, G-protein-coupled receptors; NGF, nerve growth factor; NMDA, N-methyl-d-aspartate; RGCs, retinal ganglion cells; ROS, reactive oxygen species; TNF, tumor necrosis factor; VGCCs, voltage-gated calcium channels.