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Did you ever wonder about ... Neuroprotection?
New OSN column to discuss the latest in emerging treatments and technology. In this installment, clinician-researchers discuss animal models of neuroprotection.
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A note from the editors:
This new quarterly column will address the latest research as it pertains to the practical science of glaucoma. Our first column addresses research in the area of neuroprotection.
The most highly proven and effective neuroprotective treatment for glaucoma is the lowering of IOP. When we say “neuroprotection,” we often really mean “IOP-independent treatments.” IOP-independent treatments are actively being sought in the laboratory, and one compound is already under clinical testing. A large multicenter trial to evaluate the potential of memantine as an IOP-independent treatment is ongoing, but the results are not yet available.
There have been some reports of currently available medications having neuroprotective effects beyond simply lowering IOP. To date, there are not any compelling human data validating these claims. In some studies it was difficult to separate the effect of lowering IOP from the other proposed benefit. All of the data that supports a possible IOP-independent effect come primarily from animals. Thus, when evaluating these claims, it is important for clinicians to be armed with the knowledge of the strengths and limitations of these animal models on which neuroprotective claims are based when selecting the right treatment for their patients. Because there is active research, understanding the models will help you evaluate upcoming studies and products.
Current animal models
The most commonly utilized animals are mice, rats and monkeys. There is no perfect animal model to study primary open-angle glaucoma because humans are essentially the only species known to develop an insidious adult-onset elevation of IOP which is not inflammatory, and which leads to progressive optic nerve damage. A colony of genetically isolated rhesus monkeys, which have been inbred for over 12 generations in Cayo Santiago, Puerto Rico, has been reported by Dawson and colleagues. The monkey optic nerve head is most similar to a human, but primates are difficult to study in large numbers, which are often needed to avoid artifacts induced by individual variability. For this reason, rodent models have become increasingly popular. In addition, rodents have enough similarities in the optic nerve head and retinal ganglion cell axons to allow careful study of important and clinically relevant phenomena. The DBA/2J strain of mouse (The Jackson Laboratory) also develops an adult-onset elevation of IOP; however, the clinical picture is more similar to pigment dispersion with subsequent inflammatory scarring of the trabecular meshwork.
Most animal models currently used to study glaucomatous optic nerve damage are of two general varieties – experimentally induced elevated IOP in an otherwise normal animal or direct injury of the optic nerve.
Questions about cellular events between astocytes and axons within the optic nerve head can be well studied in the rodent model. However, rats do not have a lamina cribrosa. “The lamina is not necessary for fundamental damage at the optic nerve head from elevated IOP to occur,” John Morrison, MD, said. Chronically elevated IOP in a rat causes progressive optic nerve cupping and ganglion cell axon loss (Figure 1). “The more we study the rodent model, the more similarities to the human situation we find. Rats are excellent for studying mechanisms of retinal ganglion cell deaths, but there are limitations. Because of the absence of the lamina cribrosa, rats are not ideal for studying the mechanical stresses and strains of elevated IOP at the optic nerve head,” Dr. Morrison said.
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| Normal retinal ganglion cells (arrows) and retinal ganglion cells undergoing cell death (arrowheads) in eyes with high IOP. Image: Reprinted from Am J Pathol 2005 167: 673-681 with permission from the American Society for Investigative Pathology. |
| Experimental glaucoma. The left eye has had a chronically elevated IOP induced by hypertonic saline infusion into the episcleral veins. Image: Copyright 2002 from Current Eye Research by Hanninen VA et al. Reproduced by permission of Taylor & Francis Group LLC., www.taylorandfrancis.com. |
Direct optic nerve injury models
Direct damage to the optic nerve can be performed by crushing or selectively transecting the optic nerve. Mechanical compression from a relatively elevated IOP is one of the main theories of damage at the optic nerve. Although it is traditionally thought that the compression associated with glaucoma is slowly progressive rather than sudden, these models are useful for answering certain questions – such as the possible phenomenon of secondary damage (ie, damage to axons neighboring those that were directly injured by the trauma).
However, significant differences related to the site of injury exist between direct optic nerve injury models and experimental elevated IOP models.
“With crush or transection models, you are damaging the myelinated section of the optic nerve which has a different blood supply,” Dr. Morrison said. The optic nerve head is composed of unmyelinated axons and has a unique blood supply primarily from the long posterior ciliary and choroidal vessels, with lesser contributions from the central retinal artery.
Experimentally induced elevated IOP
In the rat, the IOP is elevated by reducing aqueous outflow by ablating the trabecular meshwork, either by laser or injecting the limbal and episcleral veins with hypertonic saline. Other models use thermal cautery to obstruct aqueous veins. When done properly, the time course of the IOP elevation is subacute and chronic in nature (Figure 2).
Due to the similarity to the human condition of elevated IOP in open-angle glaucoma, elevated IOP models are usually favored but without good evidence as to the differences. Cynthia Grosskreutz, MD, PhD, has found differences in the biological consequences of increased IOP vs. optic nerve crush. In particular, calcineurin, a calcium dependent phosphatase, differs depending on the type of neural injury (Figure 3).
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“There is increasing evidence that calcineurin acts as a control point in the cell death cascade (ie, apoptosis). It is activated in experimental glaucoma and after optic nerve crush. However, calcineurin is cleaved to form an active fragment only under conditions of increased IOP,” Dr. Grosskreutz said. “This cleaved fragment of calcineurin has been implicated in other chronic conditions, such as heart failure, and its presence in glaucoma and absence following crush suggests a fundamental difference in the biological response of the eye to these insults.”
With the use of animal models, we are learning many important things about the mechanism of ganglion cell death and are testing candidates for IOP-independent treatments. Optic nerve crush and elevated IOP models are both useful for studying different aspects of neuroprotection, but there are differences between the two models. When evaluating claims of “neuroprotection,” it is important to also know which model has been used, how many animals were involved in the experiment and how closely the pressures compared between the treatment groups.
For Your Information:
- Douglas J. Rhee, MD, is an assistant professor of ophthalmology at Harvard Medical School and on the faculty of the Massachusetts Eye and Ear Infirmary. He can be reached at 243 Charles St., Boston, MA, 02144; 617-573-3670; fax: 617-573-3707; e-mail: dougrhee@aol.com.
- John C. Morrison, MD, can be reached at Casey Eye Institute, Oregon Health Sciences University, 3375 S.W. Terwilliger Blvd., Portland, OR 97237-4197; 503-494-3038; fax: 503-494-6864; e-mail: morrisoj@ohsu.edu.
- Cynthia L. Grosskreutz, MD, PhD, codirector of the glaucoma service at Massachusetts and Ear Infirmary, can be reached at MEEI, Harvard Medical School, Boston, MA; 617-573-3670; fax: 617-573-3707.