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