Neuroprotective therapies for glaucoma

Abstract

Glaucoma is the second leading cause for blindness worldwide. It is mainly caused by glaucomatous optic neuropathy (GON) characterized by retinal ganglion cell loss, which leads to visual field defect and blindness. Up to now, the main purpose of antiglaucomatous therapies has been to lower intraocular pressure (IOP) through surgeries and medications. However, it has been found that progressive GON is still present in some patients with effective IOP decrease. Therefore, risk factors other than IOP elevation, like neurotrophin deprivation and excitotoxicity, contribute to progressive GON. Novel approaches of neuroprotection may be more effective for preserving the function of the optic nerve.

Keywords: glaucoma; glaucomatous optic neuropathy; neuroprotection; retinal ganglion cells.

Figure 1

Pathogenesis of glaucoma. Notes: Glaucoma is a blindness eye disease featured by cupping of optic nerve head, loss of neuroretinal rim and thinning of RNFL. Pathological elevation of IOP is a major risk factor for development of glaucoma. Abbreviations: RNFL, retinal nerve fiber layer; IOP, intraocular pressure.

Figure 2

Retrograde transport of BDNF and neurotrophic factor deprivation in glaucoma. Notes: At synapse, BDNF is synthesized in target neurons and transported to the postsynaptic site by vesicles. There BDNF molecules are secreted into synaptic clefts, diffuse to presynaptic sides, and bind to surface TrkB receptors. The BDNF–TrkB complexes are next internalized through endocytosis, and retrograde transported to the presynaptic neuron body. In glaucoma, the retrograde transport of BDNF is obstructed, which is termed neurotrophic factor deprivation. Abbreviations: BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B.

Figure 3

Excitotoxicity induced by excess glutamate. Notes: Extensive stimulation of NMDARs by glutamate leads to high level of Ca²⁺ to enter the cell, activating enzymes including phospholipases, endonucleases, and proteases. These enzymes may lead to apoptosis of the cell. Abbreviation: NMDAR, N-methyl-D-aspartic acid receptor.

Figure 4

Molecular mechanisms of apoptotic cell death. Notes: There are two major pathways, extrinsic and intrinsic, that are responsible for apoptotic cell death. The extrinsic pathway is initiated by binding between death ligand and death receptor, while the intrinsic pathway is initiated by efflux of cytochrome c from mitochondria. The activation of these two apoptotic pathways leads to activation of downstream effectors of apoptosis caspases 3, 6, and 7. Abbreviation: Smac, second mitochondria-derived activator of caspases.

Figure 5

Overactivation of microglia around optic nerve head. Notes: Overactivation of microglia leads to excessive production of toxic materials surrounding RGCs, including TNF-α and NO. The binding between TNF-α and TNFR initiates the extrinsic apoptotic pathway, while the interaction between NO and ROS results in production of OONO⁻ followed by cell death. Abbreviations: RGC, retinal ganglion cell; TNF-α, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptor; NO, nitric oxide; ROS, reactive oxygen species.