Neuroprotective agents stem optic nerve damage by ‘offering a solution’ to open-angle glaucoma

Stefanie Petrou-Binder MD
in Berlin

ALTHOUGH it’s still early days in the clinical trials, researchers are optimistic that ‘neuroprotective’ substances will some day help prevent or reduce damage done to the optic nerve by diseases like glaucoma and other optic neuropathies.

“The need for new therapies is great. Neuroprotection could offer a solution for chronic open-angle glaucoma, in which operative and pharmacological measures to reduce intraocular pressure (IOP) are frequently not enough to stem the advancing disease process.

Cell culture showing two isolated ganglion cells from a retina of a newborn rat. One cell is still alive and has developed dendrites while the other cell has already died.

“Even though IOP is no longer the definitive factor according to the new definition of open-angle glaucoma, pressure reduction still remains the only therapeutic option,” PD Dr Wolf Lagrèze told the annual meeting of the German Society of Ophthalmology.

Neuroprotection is a treatment modality which has been gaining attention for several years. The aim of this therapy is to protect neurons within the central nervous system (CNS) from the factors thought to damage and destroy them, and uphold their function. Some approaches seek to block destructive cellular process directly, while others attempt to bolster protective processes.
The optic nerve and the retina are considered extensions of the brain and are related to the CNS both biochemically and microstructurally. The principles of neuroprotection therefore apply to ophthalmology as well, particularly in diseases involving damage to the neurons and axons of the retina.
The research specifically targets the retinal ganglion cells of the inner retina, the photoreceptors of the external retina, and the optic nerve.

Memantine
Researchers have investigated an NMDA-receptor antagonist called memantine for its efficacy in protecting the optic nerve and retina from long-term glaucomatous damage. NMDA-receptors are glutamate (one of the main neurotransmitters) receptors which also permit the influx of calcium into the cell.
Cell hypoxia, traumatic optic nerve damage and glaucoma cause glutamate to accumulate in the synaptic space by altering the physiological re-uptake process. Although itself a major neurotransmitter, elevated levels of synaptic glutamate also have a neurotoxic effect which is associated with a massive calcium current into the neuronal cells.
Calcium, in turn, activates a sequence of intracellular cascades of apoptosis (neuronal death) induction. Researchers believe memantine may prevent apoptosis by blocking retinal ganglion cell receptors.

A multicentre, randomised, double-masked, placebo-controlled clinical study is now underway to evaluate the effectiveness and safety of oral memantine in patients with chronic open-angle glaucoma at risk from glaucomatous progression.
Another promising agent, gabapentin-lactam, has been developed in Freiburg, Germany and its ability to promote retinal ganglion cell survival is currently under investigation.
It enhanced survival of rat retinal ganglion cells both in vitro and in vivo. Dr Lagrèze showed that the drug works by opening the mitochondrial ATP-sensitive potassium channels.

Two decades of research have provided detailed insights into the intracellular mechanisms of neuronal cell death. Cell apoptosis, as opposed to necrosis, refers to a genetically programmed process by which neurons seem to self-destruct within a few days without any evidence of an inflammatory reaction.
Several other apoptotic factors have been implicated. Among these is the lack of neurotrophic signals. Neurotrophic signals are sent from cell bodies embedded in the CNS to their target retinal ganglion cells in a steady stream via axonal transport. Ischaemia or optic nerve compression interfere with this transmission and cause nerve cell death.
Almost one hundred substances have shown retinal neuronal protective characteristics in in vitro tests.

NMDA-receptor antagonists, nitrous oxide synthase inhibitors, neurotrophic factors, substances which bind free radicals, glutamate-releasing inhibitors, and caspase inhibitors are central to their modes of action in counteracting the known pathophysiological mechanisms.
In vivo animal trials have proven that several of these substances have a neuroprotective effect in cases of acute retinal ischaemia and optic nerve compression as well as glaucoma models. However, the effectiveness of these substances in human patients has not been proven in any trials.

Ambiguity
Dr Lagrèze addressed the ambiguity of neuroprotective substances in clinical use. He pointed out that although animal models have proven the efficacy of some of these substances, there have not been any large clinical trials to corroborate the encouraging outcomes of the animal models.
He explained that the pathophysiological mechanisms involved in neuronal death in animals may only vaguely approximate the mechanism in people, thus rendering animal models relatively unreliable.
The high dosages and systemic application of some of the substances given in animal models make them unacceptable for use in human trials.

Coupled with that, animal models do not target complete neuroprotection, but only a certain percentage of saved neurons. The clinical relevance of animal model results has yet to be evaluated. According to Dr Lagrèze, clinical studies would need to encompass a large number of patients to achieve clinical relevance. He noted that the neuroprotective help would most likely come too late for patients suffering acute neuronal damage and that neuroprotection would probably be more advantageous in chronic disease states, such as glaucoma.

Recent findings have redefined glaucoma as an optic neuropathy associated with retinal ganglion cell loss caused by different risk factors. Some of these are elevated IOP and vascular dysregulation. However, the pathological mechanisms are not yet fully understood, and not all the risk factors are necessarily present in all forms of the disease.

As glaucoma progresses slowly, studies would need to stretch over many years to document their efficacy. Large, prolonged trials entail higher costs. Clinical trails are also afflicted by the problem that the measured parameters are subjective — that is visual acuity and visual field — and therefore subjected to high variation. Therefore, more objective visual testing methods are desirable.
He stresses that for many acute diseases affecting the CNS, such as stroke, therapy remains either unsatisfactory or nonexistent according to the criteria of evidence-based medicine.

However, Dr Lagrèze believes the application of neuroprotective substances has a potentially wide range of usage, particularly when used in combination with other neuroprotective agents.

PD Dr Med Wolf Lagrèze
University Eye Hospital, Freiburg, Germany
Email: lagreze@aug.ukl.uni-freiburg.de

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