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Issue: December 2008 Making a Case for Neuroprotection
EXPLORING The Latest Techniques and Treatments for Glaucoma

Making a Case for Neuroprotection

Researchers continue to delve into the role of neurodegeneration and apoptosis in glaucoma.

By Larry Alexander, OD, FAAO

Despite treatment, many patients with glaucoma continue to progress toward blindness. Why? One reason may be that all glaucoma patients, even those with normal IOPs, experience neurodegeneration. This degeneration is similar to that experienced in patients with neurodegenerative disorders, such as Parkinson disease, Alzheimer disease, white matter lesions and even autoimmune disorders.1

The FDA has approved only two neuroprotective drugs: one for amyotrophic lateral sclerosis and the other for severe Alzheimer disease. Articles abound about the possible neuroprotective benefits of nutritional supplements and lifestyle changes, as well as certain antioxidants, glutamate release inhibitors, calcium channel blockers, melatonin and more.2 The evidence is weak for some of these approaches, and others are just unreferenced misinformation. Currrent diagnostic imaging technology, capable of measuring ganglion cell loss in a progressive manner, coupled with having the potential of documenting intervention, will corroborate and solidify some of the claims.

In this article, I'll review what we know about apoptosis and neurodegeneration and how it may relate to glaucoma.

Neurodegenerative Process

Neurodegeneration in glaucoma is related to retinal ganglion cell loss associated with mitochondrial compromise and destruction. There's subsequent destruction of nearby cells, resulting in a progressive cascade of death with accompanying nerve fiber loss.

The process begins when pressure induces changes in the lamina cribrosa with associated pinching of the axon, stopping neurotrophin from migrating from the lateral geniculate body into the retinal ganglion cells. Neurotrophin is the lifeblood of the cell and its absence compromises enzymatic activity within the cell, tipping the balance toward mitochondrial destruction. The following factors also contribute to neurodegeneration in patients with glaucoma:

B-cell immunity: Because much of the disease process is inflammatory in nature, the immune system is actively involved. Steroids may quiet inflammation and aid in neuroprotection, but may also result in increased IOP.

Cell-mediated immunity (excess glutamate): The body needs glutamate, which modulates and mediates the neurological system. But in excess, glutamate is toxic. The key is modulation to keep all activities in balance.

Collagen abnormalities: The eye is essentially a bag of collagen, which often is affected in collagen vascular disorders and intimate associations with glaucoma. This fact is somewhat reflected by the incidence of corneal thinning as a risk factor for the progression of glaucoma and other disease processes such as retinal vein occulsion.

Endothelial dysfunction: This dysfunction creates endothelin-1, a potent vasoconstrictor, which then contributes to altered blood flow. Again, future developments in imaging technology will contribute significantly to the management of glaucoma by enabling clinicians to measure and monitor blood flow.

Vascular dysregulation: A surge of blood pressure doesn't normally affect the optic nerve because of a vascular regulation, but if patients have aberrant vascular dysregulation, then a slight change in blood pressure will affect them. In the clinic, we can't easily identify these patients at this point. The balance of blood pressure is especially important in patients with chronically depressed diastolic blood pressure as reflected in the diastolic perfusion ratio-diastolic BP – IOP, which should never be less than 30 mmHg. Again, imbalance in the "system" is critical in the genesis of glaucoma.

Insufficient antioxidant defense: Glaucomatous eyes are reported to have reduced levels of glutathione, the most prevalent antioxidant in the eye. This makes these eyes more susceptible to free radicals. All of these factors contribute to the neurodegenerative process, resulting in unplanned apoptosis or cell death. The goal of any neuroprotective drug is to reduce or delay apoptosis.3

Understanding Apoptosis

Apoptosis is a necessary part of a cell's life cycle. Each cell in the body demonstrates a variable response to apoptosis. For example, in dry eye, the lacrimal gland cells are the target of inappropriate apoptosis secondary to inflammatory products. When T-cells invade the conjunctiva, planned apoptosis shuts down and excess cells build up to inappropriately compromise tear composition. With the lacrimal gland and conjunctival goblet cells functioning improperly, the inflammatory cascade continues with a worsening of the dry eye process.

We're born with millions of ganglion cells, which we are programmed to lose over time without replacement. If survival genes block preprogrammed cell death, cancer or malformations may result. One potential goal for neuroprotective agents is to activate the genes that block inappropriate apoptosis.

Again, different cells respond differently to apoptosis. For example, CD4 and CD8 thymocytes respond to antigen receptor activation, and lymphocytes respond by dividing.

In the best scenario, there's a balance. If an apoptosis imbalance occurs, however, it triggers glutamate release, which causes still more cells to die. To reiterate: first, increased IOP causes the axons to become pinched at the lamina cribrosa, blocking entry into the ganglion cell by the neurotrophin. This causes disruption of the mitochondrial membrane. Next, excess calcium ions enter and cause a breakdown of the neurological cells. The result is cell degradation and death.4

Meeting Neuroprotective Goals

Can we drop or inject some neurotrophin into the eye and save the retinal ganglion cells? Unfortunately, the effect isn't sustainable. Only when combined with ciliary body-derived neurotrophic factor does it seem to be effective. Other possibilities include:

Receptor-site manipulation: If we manipulate the TrK receptor sites to more effectively bind with neurotrophin or inject viral cells into the eye to alter the genetic response and switch on increased neurotrophin uptake, there may be hope to stimulate the survival response. We also can attach a ligand to the neurotrophin and trick the receptors. This modulation of genetic factors isn't possible yet, but it may be an option in the future.

Caspase inhibition: Once caspase is released, it's too late to save the cells, so this approach would be ineffective.

Glutamate reduction. Through Müller cells, we can enhance the evacuation of glutamate. Several animal studies show that memantine can modulate glutamate in certain neurological disorders associated with white matter lesions. We're waiting for studies within this arena to definitively show a benefit in the eye.5

Controlled homocysteine levels: Glaucoma is associated with homocysteinemia, and elevated homocysteine levels negatively impact the vascular system and are implicated in retinal ganglion cell destruction. We can modulate this problem with folate or vitamins B6 and B12, which are readily available in multivitamins.

Mitochondrial protection. Only two known nutritional supplements actively penetrate the mitochondria and effect change: ginkgo biloba and coenzyme Q10. Acetyl L-carnitine also may be beneficial and it appears to be additive to other supplements.6

Blocking calcium channels: Betaxolol hydrochloride (Betoptic S, Alcon Laboratories Inc.) blocks calcium channels, has some IOP-lowering effects and inhibits visual field loss. Studies show it has neuroprotective potential.7

Topical Brimonidine

Some animal model studies suggest that brimonidine (Alphagan P, Allergan Inc.) may have neuroprotective effects. One study8 demonstrated that brimonidine helps maintain contrast sensitivity, which may indicate that it has neuroprotective capabilities. But it's important to note that brimonidine hasn't been proven to be neuroprotective in humans to date.

In the future, we'll see more studies about the neuroprotective benefits of various agents. Some under investigation include: glutamate receptor blockades, acetylcholinesterase inhibition, heat shock proteins, beta amyloid antibody for Alzheimer's, inhibition of nitric oxide, and delivery of growth factors. Yes, it's possible that sitting in a sauna for 15 minutes a day may create heat shock proteins to protect the visual system in glaucoma.

To successfully manage neurodegeneration, investigators will need to prove that an agent activates receptors in the retina, triggering specific protective mechanisms. It must show neuroprotective activity in animal models. Finally, when administered in practical modes in humans, it must achieve concentration at the retina, and human clinical trials must prove that the drug works. OM

Dr. Alexander is director of clinical education for Optovue and is a consultant to the John Kenyon American Eye Institute in Louisville, KY.

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