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Cell Tissue Res (2013) 353:245251

DOI 10.1007/s00441-013-1671-1

REVIEW

Neuroprotection of medical IOP-lowering therapy


Norbert Pfeiffer & Julia Lamparter & Adrian Gericke &
Franz H. Grus & Esther M. Hoffmann & Jochen Wahl

Received: 7 May 2013 / Accepted: 27 May 2013 / Published online: 9 July 2013
# Springer-Verlag Berlin Heidelberg 2013

Abstract Intraocular pressure (IOP)-lowering therapy has


been shown to arrest or retard the progression of optic
neuropathy typical for glaucoma and can, thus, be described
as neuroprotective. At present, six classes of medical therapy
are employed, namely parasympathomimetics, alpha/betasympathomimetics, -blockers, carbonic anhydrase inhibitors, 2-adrenergic receptor agonists and prostaglandin analogues. For several of these substances, some experimental
evidence exists of a possible neuroprotective mechanism,
beyond their IOP-lowering activity. -Blockers are involved
in the up-regulation of brain-derived neurotrophic factor
(BDNF) and can decrease glutamate-mediated NMDA receptor activation. Not only systemic but also topical carbonic
anhydrase inhibitors are able to increase retinal blood flow.
2-Adrenergic receptor agonists can up-regulate the formation of BDNF and anti-apoptotic factors. Prostaglandin analogues increase blood flow to the eye, possibly including the
retina. To date, evidence for a neuroprotective effect independent of IOP regulation in human glaucoma is scarce and
has only been shown to be likely for the 2-adrenergic
receptor agonist, brimonidine.
Keywords Neuroprotection . Intraocular pressure (IOP) .
IOP-lowering medication . Glaucoma

Introduction
Glaucoma is best described as a progressive optic neuropathy
of various origins. A loss of retinal ganglion cells and their
axons is accompanied by loss of visual function ultimately
leading to severe visual impairment and even blindness. At
N. Pfeiffer (*) : J. Lamparter : A. Gericke : F. H. Grus :
E. M. Hoffmann : J. Wahl
Department of Ophthalmology, Johannes Gutenberg-University,
Langenbeckstrasse 1, 55131 Mainz, Germany
e-mail: Norbert.Pfeiffer@unimedizin-mainz.de

present, glaucoma is thought to be the most common cause of


irreversible blindness worldwide. No uniformly accepted definition of glaucoma exists but most definitions involve optic
nerve damage being described as the cupping of the optic
nerve head with a typical appearance distinctly different from
other forms of optic neurodegeneration. This degeneration
also corresponds to a typical centripetal loss of the visual field.
Although by no means mandatory, an increased intraocular pressure (IOP) plays a critical role in the majority of
cases. Normal IOP is described statistically by the mean of
a normal population, which in most populations corresponds
to about 1315 mmHg plus/minus twice the standard deviation (roughly 45 mmHg). However, a large variety of vulnerability to increased IOP is now understood to occur and
glaucomatous damage might appear not only at high IOPs
but also at IOPs in the normal range or even at statistically
low pressures indicating a role of other pathomechanisms
and not IOP alone. To date, glaucoma therapy has been limited
to the lowering of IOP. Thus, for a long time, the success of
therapy has usually been measured as a decrease in IOP. Only
lately have clinical studies focused on the retardation or arrest
of the progressive loss of optic nerve structures as measured
by morphometric methods or image analysis and/or visual
function as measured by white on white perimetry. Interest
has also increased in exploring medical glaucoma therapies
with respect to their neuroprotective potential beyond their
IOP-lowering capacity. This paper reviews the potential of
medical therapy to act as neuroprotective therapy by the
lowering of IOP or by other mechanisms or by both.

Understanding glaucoma and IOP-lowering treatment


A multitude of diseases are called glaucoma. Glaucoma
might be primary or secondary, in the latter case as a result of
other ocular or systemic diseases. The most prevalent form
of glaucoma is primary open angle glaucoma (POAG),

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which, in Europe, accounts for more than 90 % of glaucoma


cases. The over-all prevalence of glaucoma is about 1 %.
However, its incidence increases sharply starting at the age
of 40 years and doubles every decade. In some populations,
the prevalence in the old age group of >85 years has been
found to be well over 15 %. Worldwide, over 60 million
individuals are estimated to be affected by glaucoma. This
figure will possibly rise to 80 million by 2020. For 2010,
about 6.7 million individuals were estimated to be totally
blind from the disease (Quigley and Broman 2006).
As about one third of glaucoma patients do not show IOPs
beyond the defined normal limits, most definitions suggest
increased IOP as being a major risk factor for developing
POAG but not as the sole cause of it. Patients that have never
had elevated IOPs but develop typical signs and symptoms
of glaucoma are usually termed as having normal tension
glaucoma (NTG).
A number of other risk factors such as race, myopia,
intake of corticosteroids, thin central corneal thickness and
a first-degree relative with glaucoma have been identified as
being associated with a higher risk of glaucoma development. However, to date, of all risk factors, IOP remains the
only modifiable and treatable risk factor for the development
and progression of glaucoma. The association of glaucoma
and increase of IOP had been noted for centuries but was
rediscovered about 150 years ago, amongst others, by
Albrecht von Graefe. Since then, the lowering of IOP was
assumed to be sufficient to stop disease progression. Hence,
various types of medical therapy and surgeries were invented
and applied to glaucoma patients. However, the usefulness of
IOP-lowering therapy was challenged as a vast proportion of
glaucoma patients were observed to have a progression of
glaucoma damage in spite of lowered IOPs. Explanations for
this paradox include the observation that some glaucoma
patients do not comply with their therapies but also that other
local or systemic factors trigger and promote the onset and
progression of glaucoma.
Large randomised studies have only recently been
conducted in order to establish whether the lowering of
IOP by either surgical or medical therapy does indeed stop
or at least retard the progression of POAG and its variants.
Such therapy that prevents the deterioration of retinal ganglion cells might be regarded as neuroprotective.

Effect of IOP-lowering therapy: landmark studies


Heijl and collaborators (2002) established in the Early
Manifest Glaucoma Trial (EMGT) that the treatment of individuals with early signs of glaucoma led to a slower progression of glaucoma than if individuals were left untreated.
The authors concluded that a reduction of IOP by 1 mmHg
would reduce the risk of progression by about 10 %.

Cell Tissue Res (2013) 353:245251

Two groups investigated whether the treatment of individuals with increased IOP but without signs of glaucoma, usually termed ocular hypertension (OHT), would prevent the
onset of POAG. The results were contradictory: Kass and
colleagues (2002) showed that, over an observation period
of 5 years, the rate of individuals progressing from OHT to
glaucoma without treatment was 9.5 %, whereas medical
treatment reduced this to 4.4 % (Ocular Hypertension
Treatment Study, OHTS). On the other hand, the European
Glaucoma Prevention Study (EGPS) failed to show such an
effect in a statistically significant proportion of participants
(Miglior et al. 2007). However, the two studies were substantially different: the EGPS had a randomised and, in addition, a
double-masked design, whereas in contrast, the OHT treatment trial was unmasked. The EGPS involved treatment with
one agent only, namely dorzolamide, whereas the OHTS
allowed multiple treatments. The double-masked EGPS
abolished observer bias. However, such a masked design did
not allow for adaptive treatment to reach a certain IOP target.
This, however, was the case with the OHTS in which medications were added until a certain IOP target had been reached.
Thus, the IOP-lowering effect in the OHTS was much greater
than that in the EGPS. Indeed, the neuroprotective effect of
IOP-lowering therapy seems to be dose-dependent considering the results from the EMGT, EGPS and OHTS thereby
emphasising the role of the lowering of IOP.
In general, surgical therapy leads to greater IOP reductions than medical therapy. Both the Advanced Glaucoma
Intervention Study and the Collaborative Glaucoma
Treatment Study (AGIS and CIGTS) have demonstrated a
larger protective effect for greater IOP reductions and lower
IOPs. Data from the AGIS have also suggested that visual
fields of glaucoma patients tend to remain highly stable if
their IOPs always range under 18 mmHg.
Most interesting are the results from the Low-pressure
Glaucoma Study Group (Krupin et al. 2011). This group
showed, in a series of observations, that the lowering of
IOP did indeed retard the progression of glaucoma, even if
previous untreated IOPs had never been elevated beyond the
range of IOP considered to be the normal. However, NTG is
thought to be a disease entity of its own, as numerous distinct
differences exist between NTG and POAG, including the
more frequent occurrence of optic disc haemorrhages, a high
prevalence of migraine, Raynauds syndrome or systemic
hypotension in NTG.
In summary, the lowering of IOP has been shown either to
prevent or at least to retard the onset of POAG. Moreover,
the lowering of IOP slows the progression of established
open angle glaucoma with either high IOP or even normal
IOP. Furthermore, the effects seem to be dose-dependent
with the lower IOPs offering better protection from the
progression of glaucoma than higher IOPs. Thus, the lowering of IOP may be regarded as neuroprotective in glaucoma.

Cell Tissue Res (2013) 353:245251

Neuroprotective mechanisms different from lowering


IOP
While IOP-lowering has now been established as neuroprotective
in glaucoma, other mechanisms have also been discussed.
Improvement of ocular perfusion could play an important
role in glaucoma treatment. Since the description of POAG,
a constant debate has raged about the pathophysiological mechanisms and also the appropriate therapy. Amongst others, the
mechanical hypothesis stressing the role of elevated IOP
and the perfusion hypothesis favouring a role of impaired
perfusion of the eyeball have been advocated. The typical
cupping of the optic nerve in glaucoma has been attributed
to mechanical stress at the lamina cribrosa giving way to
increased pressure inside the eye ball. On the other
hand, failure to stop the disease by the lowering of
IOP has lead to the hypothesis that the loss of retinal
nerve fibres could be attributable to, for example, the
reduced perfusion of critical tissues including the optic
nerve head. This controversy is by no means new.
Priestley Smith wrote in 1879: The truth of the matter
appears to be, that the glaucomatous cup is not a purely
mechanical result of exalted pressure, but is in part at
least, an atrophic condition which, though primarily due
to pressure, includes vascular changes and impaired nutrition
in the area of the disc and around its margin which require a
considerable time for their full development.
Since then and more recently, other mechanisms have
been considered to explain glaucomatous damage on a cellular or even subcellular level. A critical role has been
attributed to functional axonal transport (Anderson and
Hendrickson 1974; Minckler et al. 1976, 1977; Quigley
et al. 1981; Hollander et al. 1995; Burgoyne et al. 2005).
Increased IOP would possibly reduce normal axoplasmic
flow and, hence, transport and retrograde transport, for example, of brain-derived neurotrophic factor (BDNF) from
the synapse of the retinal ganglion cells to the cell body itself
in the retina. Thus, apart from modifying IOP and ocular
perfusion, drugs might directly affect the retinal ganglion
cell or other cell types such as glial cells (Son et al. 2010).
Again, ocular perfusion might also play a crucial role and
impaired ocular blood flow might have a critical part in the
pathogenesis of POAG (Yoshida et al. 2010; Harris et al.
1999; Bathija 2000; Zhao and Cioffi 2000). Finally, rather
than a direct effect of ischaemia, an ischaemic insult might
trigger a glutamate induced N-methyl-D-aspartate (NMDA)mediated exitotoxicity (Hiraoka et al. 2003; Kuehn et al.
2005; Rokicki et al. 2007; Osborne et al. 1999).
Some debate can be followed in the literature over whether
IOP-lowering medical therapy can address one or several of
these effects in the treatment of glaucoma. Whereas the effect
on IOP can be easily measured, a potential neuroprotective
effect is much more difficult to establish.

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Drugs that lower IOP


Drugs that lower IOP in the order in which they became
available for glaucoma treatment are the parasympathomimetics, sympathomimetics, carbonic anhydrase inhibitors,
-adrenergic receptor antagonists, 2-adrenergic receptor
agonists and prostaglandin analogues (Table 1).
Parasympathomimetics
Parasympathomimetics such as pilocarpine were the mainstay of glaucoma treatment for about a century. They lower
IOP by increasing aqueous humor outflow. This is mediated
by the constriction of the smooth muscle tissue of the ciliary
body leading to the opening of the trabecular meshwork
and Schlemms canal. Their IOP-lowering capacity is about
20 % of initial IOP. Because of their side effects of
constricting the pupil and of inducing myopia in younger
individuals, their use is limited. Evidence is lacking for a
neuroprotectie mechanism beyond their IOP-lowering
potential.
Sympathomimetics
Sympathomimetics are now used very rarely. They produce
not only a vasoconstriction of conjunctival vessels
Table 1 Classes of IOP-lowering drugs and typical examples of these
drugs
Class

Examples

Parasympathomimetics

Pilocarpine
Carbachol
Adrenaline
Dipivalyl-epinephrine
Carteolol
Timolol
Betaxolol
Metipranolol
Levobetaxolol
Acetazolamide

Sympathomimetics
-Adrenergic receptor antagonists

Carbonic anhydrase inhibitors

Doclophenamide
Dorzolamide
Brinzolamide
2-Adrenergic receptor agonists

Prostaglandin analogues

Clonidine
Apraclonidine
Brimonidine
Unoprostone
Latanoprost
Travoprost
Bimatoprost
Tafluprost

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immediately after topical application to the ocular surface


but also a reactive vasodilation. Moreover, their IOPlowering capacity is limited to only about 15 %20 % of
initial IOP. Worldwide, they are now almost out of use. At
present, they are not available in Europe and North America.
However, they show an interesting mechanism of action. In
part, they lower IOP by reducing the content of the glycosaminoglycans that are found in abundance in the trabecular
meshwork of the human aqueous outflow system.
Glycosaminoglycans seem to be increased in steroidinduced glaucoma (Johnson et al. 1990). Thus, sympathomimetics might be an interesting treatment alternative for this
secondary form of glaucoma. Intrinsic activity at both - and
-adrenergic receptors would offer potential effects on the
regulation of vasodilation. However, this has not been investigated in human glaucoma.

Carbonic anhydrase inhibitors


Carbonic anhydrase inhibitors lower IOP by blocking the
enzyme carbonic anhydrase, which is one of the three key
enzymes that are essential for the production of the aqueous
humour. Apart from their ophthalmic use carbonic anhydrase
inhibitors are weak diuretics and are only used in some
neurological disorders including mountain sickness at high
altitudes and pseudotumor cerebri. Both systemic and topical
carbonic anhydrase inhibitors inhibit carbonic anhydrase II,
which is the isoenzyme that has a major role in aqueous
humour production, which takes place in the ciliary body
epithelium in the posterior chamber. Via this mechanism,
IOP is reduced (Sugrue 2000). In addition, carbonic
anhydrase inhibitors have an influence on the buffer system
of the body. They reduce pH and hence appear to induce
vasodilation (Okazawa et al. 2001; Reitsamer et al. 2009;
Torring et al. 2009; Martinez and Sanchez-Salorio 2009).
Vasodilation in turn increases retinal perfusion (Pedersen
et al. 2005). These mechanisms might lead to an additive
neuroprotective effect beyond IOP control (for a review, see
Shih and Calkins 2012). However, the effect of carbonic
anhydrase inhibitors has not yet been shown to be superior
to other similar IOP-lowering drugs in humans. The IOPlowering effect of oral carbonic anhydrase inhibitors can be
large. Unfortunately, chronic use of the stronger systemic
carbonic anhydrase inhibitors, such as acetazolamide, is
often limited by a large spectrum of side effects including
hypokalaemia, formation of stones in the urinary tract, diuresis, pronounced sickness and aplastic anaemia. Topical
carbonic anhydrase inhibitors (dorzolamide, brinzolamide)
exhibit a much lighter spectrum of side effects. However,
because of the necessity to block >99 % of carbonic
anhydrase to lower IOP, both the duration of action and
maximal effect are limited.

Cell Tissue Res (2013) 353:245251

-Adrenergic receptor antagonists


After their introduction into ophthalmology, topical blockers quickly gained pole position in the topical treatment of glaucoma, because of their relatively mild topical
side effects. The pressure-lowering effect is roughly 25 % of
the initial IOP value and is achieved by reducing aqueous
humour production by blocking adenylate-cyclase, one of
the key enzymes of aqueous humour production. Even when
applied topically, -blockers have a considerable spectrum
of systemic side effects including systemic hypotension,
reduction of heart rate and limitation of maximal heart rate
and, potentially most dangerous, induction of bronchial constriction and asthma. Apart from the IOP-lowering effect,
several studies have suggested an indirect neuroprotective
effect of this class of substance. Betaxolol is a selective 1adrenoceptor antagonist (Cheon et al. 2003). Following
ischaemic reperfusion injury, its application exhibits a protective effect against the loss of cells from the inner plexiform layer. Timolol is a rather non-selective 1- and 2adrenoceptor antagonist. In an experimental glaucoma model in the rat, timolol had a neuroprotective effect for retinal
ganglion cells (Seki et al. 2005). The mechanism by which
-blockers are neuroprotective is uncertain. However, it
might be linked to the regulation of both calcium and sodium
channels, which play a role in the release of glutamate and,
further along the pathway, of NMDA receptors (Osborne
et al. 1997, 2004; Wood et al. 2003). Levobetaxolol appears
to be even more active, possibly by an additional upregulation of BDNF in the retina (Wood et al. 2001).
Debate continues as to whether the influence of blockers on vascular tone is neuroprotective or counterproductive. Betaxolol has been shown to increase the speed
of blood flow in the human optic nerve head. Unfortunately,
this has not been demonstrated to alter the course of
glaucoma.
2-Adrenergic receptor agonists
This group comprises mainly three substances, namely clonidine, apraclonidine (only marketed in some countries) and,
as the latest addition, brimonidine. All lower IOP by reducing aqueous humour production via the inhibition of
adenylate-cyclase, which leads to decreased cAMP levels.
In addition, they have also been shown to increase
uveoscleral outflow (Ogidigben et al. 1994; Toris et al.
1999). 2-Adrenergic receptor agonists have been used as
IOP-lowering drugs but, for a long time, interest has been
shown in a possible additional neuroprotective mechanism.
2A-Adrenergic receptors are present in the non-pigmented
ciliary epithelium and probably, thus, contribute to the regulation of aqueous humour dynamics. 2B-Adrenergic receptors are localised in axons, dendrites and glia. Finally,

Cell Tissue Res (2013) 353:245251

2C-Adrenergic receptors are found in photoreceptors


(Woldemussie et al. 2007).
Brimonidine and other 2-adrenergic receptor agonists
have shown promise as being neuroprotective, as has been
demonstrated by a variety of models, especially in the optic
nerve crush model (Wheeler et al. 1999; Yoles et al. 1999;
Pinar-Sueiro et al. 2011). Thus, brimonidine has been suggested also to be neuroprotective in glaucoma (Saylor et al.
2009). At this time, brimonidine is the only agent for which a
positive neuroprotective effect has been shown to occur in
human glaucoma.
Further evidence has been produced from the Lowpressure Glaucoma Study Group (Krupin et al. 2011). The
investigators randomised their patients into two groups. The
first group was treated with topical brimonidine, whereas the
second group was treated with topical timolol, a nonselective IOP-lowering -blocker. IOP lowering was similar
in both treatment groups. However, the preservation of visual function as measured by white on white perimetry was
better in the brimonidine group. The authors concluded that
brimonidine might preserve visual function by a mechanism
that is not described by IOP lowering alone but, at least in
part, by another mechanism beyond this, i.e., it has a
neuroprotective effect in its own right.
The possible underlying mechanism for such a
neuroprotective effect is not known. Brimonidine has been
shown to up-regulate BDNF in retinal ganglion cells (Gao
et al. 2002). However, brimonidine has various other effects
and side effects that might be involved in such mechanisms.
Nevertheless, for the time being, it remains the only topical
glaucoma therapy for which a possible neuroprotective effect
other than the lowering of IOP alone has been demonstrated
in human glaucoma.
Prostaglandin analogues
Prostaglandin analogues were introduced into ophthalmology about 12 years ago. They quickly gained widespread
acceptance for various reasons. They are very powerful
IOP-lowering agents. In contrast to topical -blockers and
-adrenergic medications, they have next to no systemic side
effects. Moreover, they need to be applied only once daily,
which appears to enhance patient compliance considerably.
Pressure-lowering effects of most of the agents is about
25 %30 % of initial IOP with the exception of unoprostone,
which is much less powerful. This drug is now mainly
marketed in Japan. Prostaglandin analogues are also considered to be the most powerful of all IOP-lowering drugs.
Local side effects include ocular hyperaemia, inflammation,
ocular intolerance and possibly ocular surface disease.
Lengthening of eye lashes and irreversible darkening of the
iris at the moment are considered as rather intriguing but
otherwise probably harmless side effects.

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Prostaglandin analogues lower IOP by increasing


uveoscleral outflow. However, recent evidence also suggests
that they increase conventional outflow via the trabecular
meshwork and Schlemms canal. In addition, a direct
neuroprotective effect has been shown by Kanamori et al.
(2009) who demonstrated that retinal ganglion cells are
protected from apoptosis both in vitro and in vivo by this
drug. Moreover, glutamate toxicity seems to be antagonised
by latanoprost (Zheng et al. 2011; Nakanishi et al. 2006).
Another suggestion is that a direct neuroprotective (antiapoptotic) effect might be induced by the protein kinase
pathway triggering neurite outgrowth and caspase-3 inhibition. Additionally, prostaglandin analogues can induce vasodilation possibly leading to increased ocular perfusion. In
spite of the worldwide use of prostaglandin analogues and
the plethora of literature, no evidence has been presented to
date for a neuroprotective effect of prostaglandin analogues
in humans, apart from their IOP-lowering capacity.

Concluding remarks
Glaucoma appears to be an enigma. When first described, it
was thought to be a disease that was precipited by increased
IOP attributable to various origins inducing the cupping of
the optic disc purely by mechanical stress. However, almost
at the same time, the idea was conceived that glaucoma
might be a primary optic nerve disease that makes it only
more prone to respond to risk factors such as increased IOP.
Indeed, good arguments for both views can still be made.
OHT is about eight times more prevalent than glaucoma.
This is a condition in which IOP is increased above normal
limits but optic nerve damage does not occur or has not
occurred as yet. A mechanism leading to glaucoma independent of IOP is supported by the observation that some patients present with typical optic disc cupping and a typical
loss of visual function on perimetry but have apparently
never had elevated IOP.
Only recently, studies have demonstrated convincingly
that the lowering of ocular pressure seems to be helpful in
all conditions: in patients with elevated IOP and
glaucomatous optic nerve cupping, in patients with such
nerve cupping without elevated IOP and finally also in individuals with elevated IOP. Under IOP-lowering treatment,
patients develop glaucoma less frequently. Thus, the lowering of IOP by means of medication and probably also by
surgical therapy appears to be neuroprotective for the optic
nerve in the human eye.
A multitude of pharmacological substances have been
shown to have neuroprotective properties in various models
including those that concern the optic nerve. Some of them
also lower IOP, which, for example, in the case of the optic
nerve crush injury model, probably does not play a major

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role. Of all topical or systemic pressure-lowering agents that


are nowadays used in the treatment of human glaucoma, only
brimonidine appears to have a mechanism that is independent of IOP lowering and neuroprotective for the optic nerve
in human glaucoma. The evidence is not complete.
Brimonidine treatment is superior over either timolol or
argon-laser-trabeculoplasty treatment, although both timolol
and argon-laser trabeculoplasty treatment exhibit an equal or
greater IOP-lowering effect. However, timolol, for example,
has well-known systemic side effects including bradycardia
and systemic hypotension, which are present in many patients that receive topical timolol therapy. Thus, the IOPlowering neuroprotective effect might be counter-acted by
reduced ocular perfusion caused by systemic hypotension or
bradycardia. Such a systemic effect has not been described
for argon-laser trabeculoplasty. Again, a topical side effect
such as intraocular inflammation caused by laser treatment
might counter-act the IOP-lowering effect of that laser procedure. However, the eventual establishment of a
neuroprotective effect in human glaucoma will need to come
from large randomised studies in patients with wellphenotyped glaucoma and sufficient (>5 years) follow-up
with both morphometric measurements of the optic nerve
and functional test endpoints.

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