Articles
Neuroprotection in Relation to Retinal Ischemia and Relevance to Glaucoma☆

https://doi.org/10.1016/S0039-6257(99)00044-2Get rights and content

Abstract

Management of glaucoma is directed at the control of intraocular pressure (IOP), yet it is recognized now that increased IOP is just an important risk factor in glaucoma. Therapy that prevents the death of ganglion cells is the main goal of treatment, but an understanding of the causes of ganglion cell death and precisely how it occurs remains speculative. Present information supports the working hypothesis that ganglion cell death may result from a particular form of ischemia. Support for this view comes from the fact that not all types of retinal ischemia lead to the pathologic findings seen in glaucomatous retinas or to cupping in the optic disk area. Moreover, in animal experiments in which ischemia is caused by elevated IOP, a retinal abnormality similar to that seen in true glaucoma is produced, whereas after occlusion of the carotid arteries a different pattern of damage is found. In ischemia, glutamate is released, and this initiates the death of neurons that contain ionotropic glutamate (NMDA) receptors. Elevated glutamate levels exist in the vitreous humor of patients with glaucoma, and NMDA receptors exist on ganglion cells and a subset of amacrine cells. Experimental studies have shown that a variety of agents can be used to prevent the death of retinal neurons (particularly ganglion cells) induced by ischemia. These agents are generally those that block NMDA receptors to prevent the action of the released glutamate or substances that interfere with the subsequent cycle of events that lead to cell death. The major causes of cell death after activation of NMDA receptors are the influx of calcium into cells and the generation of free radicals. Substances that prevent this cascade of events are, therefore, often found to act as neuroprotective agents. For a substance to have a role as a neuroprotective agent in glaucoma, it would ideally be delivered topically to the eye and used repeatedly. It is, therefore, of interest that betaxolol, a β-blocker presently used to reduce IOP in humans, also has calcium channel-blocking functions. Moreover, experimental studies show that betaxolol is an efficient neuroprotective agent against retinal ischemia in animals, when injected directly into the eye or intraperitoneally.

Section snippets

Ganglion Cells: Sole Neurons Affected in Glaucoma?

Ophthalmoscopic observations made on the eyes of patients with glaucoma have revealed an alteration in the optic nerve head appearance with loss of the reflections from the retinal nerve fiber layer.169, 211 These data point to the widespread death of ganglion cells and suggest also that the remainder of the inner retina and the outer retina are relatively unaffected. Subsequent studies, particularly with regard to the electroretinogram (ERG), have supported this view. It is known that any

Ischemia: Role in Glaucoma?

The pathologic pathway initiated by an ischemic-like insult that leads to cell death is summarized in Fig. 2. Information on the existence of such a pathway has been generated from many experimental studies relating to the prevention of stroke and ischemic brain disease.193, 194, 195 Although the details of the pathway are certainly incomplete, there is compelling evidence to suggest that neurons, which contain ionotropic glutamate receptors (e.g., NMDA receptors), are particularly susceptible

Cupping in Glaucoma: Caused by Ischemia?

Optic disk cupping is a major clinical sign for detecting and monitoring the progression of glaucomatous optic neuropathy. Yet, the cause(s) of optic disk cupping has always remained a matter of controversy, because a number of hypotheses have been proposed to account for the observed changes.46 Essentially, opinion is divided between the merits of two theories: mechanical and vascular. According to the mechanical theory, elevated IOP leads to direct compression and/or shearing of axons and the

Ischemia of a Certain Type Is Associated Only With Glaucoma

Ischemia is defined as an arrest of blood flow and consequent reduction of oxygen supply. The supply of oxygen to the retina is controlled by a retinal and choroidal blood flow. A local store of oxygen may also be associated with the vitreous humor. The entire choroidal or retinal blood supplies are not likely to be affected in the same way. As a consequence, ischemic damage to the various components of the retina may depend on the nature of the ischemic insult. Raising the IOP may compromise

Diseases Other Than Glaucoma in Which Ganglion Cells Are Affected

A crucial feature of glaucoma is the progressive death of retinal ganglion cells. Ganglion cell death is also a feature of a number of other optic neuropathies and retinopathies, and, as with glaucoma, some of these disorders have an ischemic cause. It is, therefore, pertinent to question whether there are any similarities among glaucoma and these other diseases in relation to the pathophysiology or biochemistry of the retina. Unfortunately, there are few conclusive data available on this

Cell Death by Apoptosis in Experimental Retinal Ischemia and Glaucoma

Ischemic neuronal death has traditionally been attributed to necrosis.35 Recently, morphologic studies have characterized two distinct types of cell death: necrosis and apoptosis. However, traditionally it has not been easy to ascribe one specific form of cell death to a given situation, particularly in a pathologic tissue, with the result that various authors have described cell death as by “secondary necrosis,” “intercurrent apoptosis and necrosis,” “sequential apoptosis/necrosis,” or

Possible Causes of Ganglion Cell Death

Experimentally, ganglion cells in the retina can be induced to die in a variety of ways. However, no study has demonstrated unequivocally a method to kill solely ganglion cells in vivo. The most selective way of killing ganglion cells would appear to be by transection of the optic nerve. Whether all ganglion cells die at the same rate by this procedure has not been clearly shown. Efferent fibers are known to exist in the optic nerve, particularly in nonmammalian species, and they directly

Strategies for the Potential Arrest of Ganglion Cell Death

It is clear from the previous sections that numerous factors play a role in the loss of the retinal ganglion cells in glaucoma, and it is more than likely that these act in concert to produce the overall pathologic findings associated with the disease. It follows that agents that interfere with any or all of these processes will alleviate, at least to some extent, the damage to the ganglion cells. Thus, a neuroprotectant might act to 1) halt the initial energy loss, 2) maintain the integrity

Protection of Ganglion Cells in Ischemia With NMDA Antagonists

Glutamate is released from the retina after ischemia by raising the IOP and as a consequence of glaucoma.41 This can lead to destruction of the ganglion cells by overactivation of their ionotropic gluta mate receptors (see above). It would appear from a variety of studies that NMDA-type glutamate receptors play a particular part in excitotoxicity of ganglion cells. Thus, in theory, NMDA antagonists should prevent ganglion cell damage by ischemia, and this has been shown to be true in

Protection of Ganglion Cells in Ischemia by Reducing Free Radical Effects

Production of oxygen free radicals follows as a natural consequence of aerobic metabolism because these species are generated continuously in vivo by cellular chemical reactions.34 Oxygen free radicals are, by definition, species with an unpaired electron associated with oxygen, e.g., •O2−, •OH, NO•, ONOO−. Oxygen free radicals and reactive oxygen species (ROS) can react detrimentally with most macromolecular cellular constituents and may lead to protein conversion, lipid peroxidation, or

Protection of Ganglion Cell Injury by Preventing Excessive Influx of Ca2+

The concentration of Ca2+ in the cytosol of unstimulated neurons is maintained between 0.05 and 0.2 μM. Extracellular Ca2+ levels exist at approximately four orders of magnitude higher. This produces a large, inwardly directed, electrochemical driving force that is primarily balanced by active Ca2+ extrusion through the plasma membrane and by the coordinated activity of Ca2+-sequestering systems located in the mitochondrial, endoplasmic reticular, and nuclear membranes. In addition,

Ideal Drug for Treatment of Glaucoma

The ideal glaucoma drug would be one that can be taken orally, prevent ganglion cell death, and have no side effects to the patient. Should the patient also have increased IOP, this can be treated separately. However, in reality, any drug not targeted specifically to the retina to prevent ganglion cell death is likely to have appreciable side effects. Therefore, at this stage of our thinking, a more likely ideal drug for glaucoma would be one that can be applied topically, reduce IOP, reach the

Method of Literature Search

Relevant references were identified by searching MEDLINE and Current Contents, using a range of different search words alone or in combination. These included apoptosis, calcium, excitotoxicity, free radical damage, ganglion cells, glaucoma, glutamate, optic nerve damage, retina, and retinal ischemia. Additional articles were obtained from the reference lists of key articles and reviewed. An attempt was made to include all references relevant to neuroprotection and retinal ischemia/glaucoma

Acknowledgements

Supported in part by the International Glaucoma Association, London.

We are grateful to Professors S. M. Pedos (New York) and P. L. Kaufman (Wisconsin) for providing valuable suggestions in the writing of this article.

Reprint address: Prof. N. N. Osborne, The Nuffield Institute of Ophthalmology, Walton Street, Oxford OX2 6AW, United Kingdom.

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    The authors did not indicate any proprietary or commercial interest in any product or concept discussed in this article.

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