








































Bangladesh Journal of Medical Science Vol.09 No.4 Jul’10 

*Corresponds to: Dr. Md. Nurul Islam, Assistant Professor, Islami Bank Medical College, Rajshahi. Email: 
dr.nuruleye.bd@gmail.com. 
 

Review Article 

Management of glaucoma with neuroprotective drug 
 

Islam N* 
 

Abstract 

Glaucoma is an optic neuropathy characterized by progressive loss of retinal ganglion 
cells (RGCs). Death of ganglion cells is not always only pressure dependent mechanism 
but also have several pressure independent mechanism that establish a cascade of changes 
that ultimately leads to cell death.  
Neuro- protection is a process that attempt to preserve the cells that were spared during 
initial insult, but are still vulnerable to damage. Although not yet available, a 
neuroprotective   agent would be great use that rescue neurons already compromised or 
that promote regrowth of axonal or dendritic connection to restore function. 
This review based on literature, giving the idea of varies mechanism of RGC death 
delineated by research and discussed some pharmacological agent believed to have a 
neuroprotective role in glaucoma. 

Introduction
Glaucoma is a neurodegenerative disease 
in which intraocular pressure (IOP) is a 
leading risk factor1,2. Despite IOP 
lowering, glaucoma continues to worsen in 
a subset of patients2-5. The final stage in 
glaucoma involves retinal ganglion cell 
(RGC) damage and death2. This damage 
can occur at statistically high, average, or 
low levels of IOP. While the biomechanics 
of optic disc cupping specifically, loss of 
neuroretinal rim and posterior bowing of 
the lamina cribrosa have been extensively 
studied6,7. They do not adequately explain 
why certain patients continue to 
demonstrate worsening of the disease in 
spite of apparently low IOP. In addition to 
IOP, several other triggers are 
hypothesized to contribute to RGC axonal 
injury and death8. 
 
These triggers include loss of neurotrophic 
factors, localized ischemia, excitotoxicity, 
alterations in immunity, and oxidative 
stress. There is increasing evidence that 
these factors, triggered by high IOP or 
occurring independently of IOP, may 
contribute to affecting the optic nerve. 
 
Basis of neuroprotection 

Glaucoma is an axonal disease in which 
Retinal ganglion cell (RGC) axons are the 
initial site of damage. According to the 
biomechanical model of damage, structural 
failure of laminar beams and strain along 
the retinal nerve fiber layer lead to axonal 
damage. Damaged axons then degenerate 
via apoptosis (an energy-requiring form of 
cell death) either in a retrograde fashion or 
by Wallerian degeneration. Axonal 
transport is disrupted primarily at the level 
of the lamina cribrosa9,10. A decrease in the 
axonal blood flow follows mechanical 
injury and death of RGCs9,10. The exact 
pathophysiology of axonal injury and death 
remains unclear; however, a variety of 
inter and intra-cellular events are triggered 
during the process of cell death, and these 
events may be potential targets of 
neuroprotective strategies. In many 
neurologic diseases, injury can spread to 
connected neurons by a mechanism called 
transsynaptic degeneration. The 
surrounding axons may undergo apoptosis 
because of the loss of certain neurotrophic 
factors, such as brain-derived neurotrophic 
factor and nerve growth factor11,12. On the 
other hand, surrounding axons may be 
exposed to upregulated factors that lead to 
cytotoxicity, such as tumor necrosis factor-



N Islam 

200 

a (TNF-a) 13,14.  It is unclear whether the 
process of transsynaptic degeneration 
affects only surrounding RGC axons or 
whether afferent neurons within the inner 
retina may also be affected. 
 
Inhibition of intracellular calcium ion 
(Ca2+) uptake has been a major focus of 
glaucoma neuroprotection because an 
increase in intracellular Ca2+ is associated 
with RGCs degeneration. Calcium enters 
cells through voltage-gated channels and 
N-methyl-d-aspartate (NMDA) glutamate 
receptor associated channels. An increase 
in intracellular Ca2+ activates calcineurin, 
Which causes the release and activation of 
apoptotic mediators, such as caspases from 
mitochondria into the cytoplasmic 
space15.Cytoplasmic Ca2+ also stimulates 
nitric oxide production. The upstream 
trigger for this cascade of events may be 
glutamate dependent. Neuroprotection in 
glaucoma is the targeted treatment of 
neurons of the visual pathway (particularly 
RGCs) that are damaged in the 
glaucomatous process. 
 
 In neuroprotection, the goal is to directly 
stimulate or inhibit specific biochemical 
pathways that either prevent injury or 
stimulate recovery of these neurons. 
Indirect treatments, such as IOP lowering, 
by definition are not neuroprotection. 
Retinal ganglion cell njury may occur by a 
variety of pathophysiologic mechanisms 
including increased intraocular pressure, 
ischemia, genetic factors, and failure of 
trophic support. Conventional treatment to 
prevent optic neuropathy has focused on 
preventing or mitigating the effect of the 
inciting factor. Neuroprotection in 
glaucoma involves targeted modification of 
NMDA receptor and promotes Ca2+ 
uptake16. An increase in intravitreal 
glutamate causes RGC death in vitro; 
however, an increase in intravitreal 
glutamate has not been observed in 
experimental models of glaucoma17. 
Glutamate toxicity has also been shown to 

lead to degeneration of postsynaptic 
neurons in the lateral geniculate nucleus18. 
 
Neuroprotective medications 
There are several theoretically effective 
neuroprotective therapies that 
unfortunately remain somewhat limited in 
practice. While cell culture results with 
brain-derived neurotrophic factor have 
been promising, its effect is only transient, 
which may possibly be due to receptor 
turnover19. Altering the expression of 
apoptosis proteins is possible in transgenic 
animals, but it cannot be easily achieved or 
controlled in humans20. Finally, 
experimental models of RGCs axonal 
injury (cell cultures and murine or primate 
models) do not entirely reproduce the 
multifactorial pathophysiologic events of 
glaucoma in humans. Nevertheless, strong 
experimental Evidence for certain 
medications may lead to clinical use in the 
near future. 
 
Memantine 
Memantine is an NMDA receptor 
antagonist that blocks the excite toxic 
effects of glutamate21. The drug has been 
used to treat Parkinson’s and Alzheimer’s 
disease22. Glutamate-mediated synaptic 
transmission is critical for normal 
functioning of the nervous System; 
however, if neurons are injured and unable 
to properly control the regulation or 
clearance of glutamate, secondary excite 
toxic damage can result. Under pathologic 
conditions, the NMDA receptor is over 
activated and excessive Ca2+ influx 
occurs23. Therefore, oral Memantine 
theoretically may benefit patients with 
progressive glaucoma. Memantine has 
been shown to protect RGCs and brainstem 
neurons in a monkey model of glaucoma24. 
However, a recent report from a Phase III 
clinical trial indicates that Memantine 
failed to show efficacy compared with 
placebo when used in patients with 
glaucoma25.Given the results of this trial, 
the exact role of Memantine in glaucoma 
patients remains unclear. We currently 



Management of glaucoma with neuroprotective drug 

201 

counsel patients who show 
stereophotographic or perimetric 
progression of glaucoma despite 
maximally tolerable IOP lowering therapy 
about the absence of additional clinically 
proven therapies for glaucoma. Because of 
the safety profile of Memantine and its 
theoretical benefit in preventing axonal 
injury, patients in whom standard medical 
or surgical therapy is ineffective or not 
possible are offered treatment with 
Memantine. 
 
Brimonidine 
In addition to lowering IOP, alpha-2 
adrenergic receptor agonists also increase 
release of neurotrophic factors, inhibit 
glutamate toxicity, and reduce Ca2+ uptake 
by neurons in both in vitro and in vivo 
animal models26,27. This class of 
medication may also inhibit activation of 
proteins involved in apoptosis28. Alpha-2 
receptors are found in a variety of retinal 
locations and are expressed in RGCs29. 
Topically administered alpha-2 agonists, 
such as Brimonidine, have been found to 
achieve neuroprotective intravitreal 
concentrations30. The efficacy of 
Brimonidine in normal-tension glaucoma 
patients is currently being evaluated 
prospectively. 
 
However, the neuroprotective effect of 
Brimonidine remains controversial given 
the medication’s accompanying IOP-
lowering effect. A clinician also cannot a 
priori determine whether glaucomatous 
damage is due to a pressure-dependent or 
pressure-independent process. As such, we 
do not use Brimonidine as a first-line 
treatment for glaucoma when other 
medications are tolerated, nor do we use 
Brimonidine for a neuroprotective effect. 
Further studies are needed to determine the 
utility of Brimonidine in glaucoma 
neuroprotection. 
 
Betaxolol  

Selective beta-1 adrenergic antagonists 
(Betaxolol) have a similar neuroprotective 
effect in vitro as the alpha-2 agonists. 
Betaxolol increases neurotrophin levels, 
decreases intracellular Ca2+, and blocks 
glutamate excitoxicity31.However, the 
concentrations required to achieve this 
effect are nonpharmacologic32. Topical 
administration does not appear to achieve 
necessary intravitreal neuroprotective 
concentrations. As such, currently 
available topical beta-1 adrenergic 
antagonists should not be used for 
glaucoma neuroprotection.  
 
Calcium channel blockers 
Systemic calcium channel blockers (CCB) 
cause vasodilation by preventing the 
intracellular uptake of Ca2+. CCB may 
improve optic nerve head perfusion, 
particularly in patients with normal-tension 
glaucoma33. While CCBs have been shown 
to improve psychophysical testing in a 
small group of patients, these results have 
not been confirmed in a large study34. Side 
effects associated with systemic CCBs may 
limit their practical use. In a small group of 
patients placed on systemic nifedipine, a 
significant number were intolerant of the 
medication and had to discontinue it35. A 
recent prospective population-based study 
has also shown a positive correlation 
between systemic CCB use and the 
development of incident glaucoma. Further 
prospective studies are needed to 
determine the safety and efficacy of CCBs. 
We presently do not make 
recommendations to glaucoma patients 
regarding the use of CCBs. 
 
Conclusion 
The concept of direct optic nerve 
protection is in its infancy. Nonetheless 
research in to inventive delivery –systems 
improved safety and discovery of 
additional neuroprotective agents will 
undoubtedly lead us further in to this 
promising era in glaucoma therapy. 

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N Islam 

202 

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