Role of Alpha-2 Agonists in Neuroprotection

Abstract

Four criteria are used to evaluate the potential usefulness of an agent for neuroprotection in glaucoma: 1) the agent must have a target in the retina; 2) it must be neuroprotective in animal models; 3) it must reach neuroprotective concentrations in the posterior segment after clinical dosing; and finally, 4) it must be shown to be neuroprotective in clinical trials. The alpha-2 adrenergic agonist brimonidine has met the first three criteria and clinical trials to establish the fulfillment of the fourth criterion are ongoing. The effects of brimonidine are mediated by its interaction with alpha-2 adrenergic receptors that are present in the retina. Activation of alpha-2 receptors by brimonidine has been shown to effectively promote the survival and function of retinal ganglion cells in a variety of animal models of optic injury relevant to glaucoma such as the chronic ocular hypertensive rat and rat optic nerve crush. Brimonidine has also been shown to be neuroprotective in the rat ischemia reperfusion model that evaluates general hypoxic damage to the whole retina. Clinical dosing of the topical formulation of brimonidine results in brimonidine concentrations in the posterior segment that are sufficient for both pharmacological activity at alpha-2 adrenergic receptors and neuroprotection. Finally, clinical trials are in progress to investigate the ability of brimonidine to protect human retinal ganglion cells and the visual field in glaucoma-related disease.

Introduction

Glaucoma is a progressive optic neuropathy. Many factors, including high intraocular pressure (IOP), vascular insufficiency, and metabolic disturbances, may contribute to the development of this disease. Although different types of glaucoma may have diverse etiologies, glaucoma is invariably characterized by accelerated retinal ganglion cell (RGC) death.10, 16

Recently, there has been a new understanding of how RGCs die in glaucoma patients. Glaucomatous RGC death has been shown to be apoptotic rather than necrotic.6, 14 Apoptosis is a genetically and biochemically controlled process that progresses in a step-by-step fashion, in contrast to cell death by necrosis.¹³ The release of cytochrome C from mitochondria is an important step in the apoptotic pathway, because cytochrome C activates a caspase cascade that results in the proteolytic degradation of the cell leading to apoptosis. Members of the BCL-2 (B cell lymphoma-2) family play a crucial role in regulating mitochondrial membrane permeability and cytochrome C release. BCL-X_L and BCL-2 are present in the retina and are anti-apoptotic because they prevent cytochrome C release; BAD (BCL-2 associated death promoter) and BAX (BCL-2 associated x protein) are pro-apoptotic because they increase mitochondrial membrane permeability and cytochrome C release.¹⁵ They do this by forming a dimer with either BCL-2 or BCL-X_L and inactivating them. Phosphorylation of BAD prevents its dimerization with BCL-2 or BCL-X_L and prevents apoptosis.²²

Anti-apoptotic signals, such as growth factors, promote RGC survival; pro-apoptotic signals, including elevated IOP and ischemia, induce RGC death. The survival of RGCs is dependent on a delicate balance between these cell survival and cell death signals,¹¹ and apoptosis is triggered when the balance is tipped in favor of cell death. Research in animal and cell culture models has shown that manipulations that counteract these signal imbalances can block key steps in apoptosis and prevent cell death. It is anticipated that in the future, RGC death in glaucoma may be prevented by using a strategy of neuroprotection to tip the balance in favor of cell survival.¹⁶

The goal of neuroprotection research in glaucoma is to identify and develop drugs that can prevent RGC death by either blocking cell death signals or enhancing cell survival signals. The purpose of this review is to describe the criteria used to evaluate potential neuroprotective agents for clinical use and to present evidence that brimonidine may be a promising neuroprotective therapy.