Neuroprotective Agents in Glaucoma Therapy: Future Directions
Glaucoma, globally the second most common cause of blindness and the commonest cause of preventable visual disability, is a progressive neurodegenerative disease of the retinal ganglion cells and their axons. While reduction of intraocular pressure remains the clinician's principal method to treat this disease, such treatment is often only partly effective, or provokes unacceptable treatment-associated comorbidities. An alternative treatment paradigm is required to manage this problem more effectively. Neuroprotection aims to protect as yet undamaged, and to rescue already damaged neurons, from the glaucoma insult(s) to retinal ganglion cells. It has the potential to prevent retinal ganglion cell death independently of the particular factors that damage the optic nerve. Research laboratories worldwide have reported exciting developments in the search for potential neuroprotective agents. This article reviews what is known to date, as well as possible future directions.
Globally, glaucoma is the most common optic neuropathy, the second most common cause of blindness and the most common cause of preventable visual disability. It encompasses a spectrum of progressive optic neuropathies characterized by pathological degeneration of nonmyelinated retinal ganglion cells (RGCs), with structural damage at the optic nerve head. Irrespective of the multitude of potential initiating insults, the common theme in the pathogenesis of glaucoma is the triggering of a cascade that results in accelerated apoptosis of the RGCs. This process of cellular death occurs in the absence of inflammation, and is characterized by DNA fragmentation, chromosome clumping, cell shrinkage and membrane blebbing. As a consequence of neuronal death within the central visual pathway, clinical signs of glaucoma include retinal nerve fiber layer defects, neuroretinal rim thinning with excavation of the optic nerve head ('cupping') and irreversible visual field loss. Neural degeneration in glaucoma is not limited to the retina; it also affects neurons in the lateral geniculate nucleus and visual cortex.
Although intraocular pressure (IOP) is no longer part of the definition of glaucoma, it is the most easily modifiable risk factor to decrease both risk of disease onset and disease progression. IOP reduction by medical, laser surgical means remains the only clinically proven treatment for glaucoma, but it is not entirely effective for all patients, as exemplified in the Collaborative Normal Tension Glaucoma Study: despite IOP reduction, glaucomatous optic degeneration continued, albeit more slowly and in a smaller proportion of patients. Sufficient IOP reduction to arrest the disease process entirely may be difficult, or may provoke significant adverse side effects. These inadequacies in our current treatment paradigm have prompted research into neuroprotection as an alternative strategy for glaucoma.
Neuroprotection has been investigated against several neurological diseases: Alzheimer's disease, Parkinson's disease, stroke, spinal cord injury and amyotrophic lateral sclerosis. The processes killing neurons in these conditions overlap with those proposed to occur in glaucoma: hypoxia, trophic insufficiency, oxidative stress, excitotoxicity, immune-related attack and apoptotic death. Agents that benefit these neurodegenerative disorders may also assist in glaucoma.
Abstract and Introduction
Abstract
Glaucoma, globally the second most common cause of blindness and the commonest cause of preventable visual disability, is a progressive neurodegenerative disease of the retinal ganglion cells and their axons. While reduction of intraocular pressure remains the clinician's principal method to treat this disease, such treatment is often only partly effective, or provokes unacceptable treatment-associated comorbidities. An alternative treatment paradigm is required to manage this problem more effectively. Neuroprotection aims to protect as yet undamaged, and to rescue already damaged neurons, from the glaucoma insult(s) to retinal ganglion cells. It has the potential to prevent retinal ganglion cell death independently of the particular factors that damage the optic nerve. Research laboratories worldwide have reported exciting developments in the search for potential neuroprotective agents. This article reviews what is known to date, as well as possible future directions.
Introduction
Globally, glaucoma is the most common optic neuropathy, the second most common cause of blindness and the most common cause of preventable visual disability. It encompasses a spectrum of progressive optic neuropathies characterized by pathological degeneration of nonmyelinated retinal ganglion cells (RGCs), with structural damage at the optic nerve head. Irrespective of the multitude of potential initiating insults, the common theme in the pathogenesis of glaucoma is the triggering of a cascade that results in accelerated apoptosis of the RGCs. This process of cellular death occurs in the absence of inflammation, and is characterized by DNA fragmentation, chromosome clumping, cell shrinkage and membrane blebbing. As a consequence of neuronal death within the central visual pathway, clinical signs of glaucoma include retinal nerve fiber layer defects, neuroretinal rim thinning with excavation of the optic nerve head ('cupping') and irreversible visual field loss. Neural degeneration in glaucoma is not limited to the retina; it also affects neurons in the lateral geniculate nucleus and visual cortex.
Although intraocular pressure (IOP) is no longer part of the definition of glaucoma, it is the most easily modifiable risk factor to decrease both risk of disease onset and disease progression. IOP reduction by medical, laser surgical means remains the only clinically proven treatment for glaucoma, but it is not entirely effective for all patients, as exemplified in the Collaborative Normal Tension Glaucoma Study: despite IOP reduction, glaucomatous optic degeneration continued, albeit more slowly and in a smaller proportion of patients. Sufficient IOP reduction to arrest the disease process entirely may be difficult, or may provoke significant adverse side effects. These inadequacies in our current treatment paradigm have prompted research into neuroprotection as an alternative strategy for glaucoma.
Neuroprotection has been investigated against several neurological diseases: Alzheimer's disease, Parkinson's disease, stroke, spinal cord injury and amyotrophic lateral sclerosis. The processes killing neurons in these conditions overlap with those proposed to occur in glaucoma: hypoxia, trophic insufficiency, oxidative stress, excitotoxicity, immune-related attack and apoptotic death. Agents that benefit these neurodegenerative disorders may also assist in glaucoma.
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