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Experimental and Clinical Evidence for Brimonidine
as an Optic Nerve and Retinal Neuroprotective Agent

An Evidence-Based Review
Meredith Saylor, BA; Linda K. McLoon, PhD; Andrew R. Harrison, MD; Michael S. Lee, MD Objective: To review the available evidence for the neu-
for neuroprotection: receptors on its target tissues, ad- roprotective qualities of brimonidine tartrate in optic nerve equate penetration into the vitreous and retina at phar- macologic levels, and induction of intracellular changesthat enhance neuronal resistance to insults or interrupt Methods: References for this study were obtained by run-
apoptosis in animal models. Brimonidine did not meet ning a search of the PubMed database using keywords the final neuroprotective criterion of success in humans.
brimonidine, neuroprotection, ischemic optic neuropathy,and ␣2-adrenergic agonists. References focusing on ocu- Conclusions: Experimental evidence has demon-
strated that brimonidine is a potential neuroprotectiveagent. However, to date, clinical trials have failed to trans- Results: Forty-eight articles addressing 1 of 4 criteria
late into similar efficacy in humans.
for neuroprotection were included. The literature con-firms that brimonidine therapy meets the first 3 criteria Arch Ophthalmol. 2009;127(4):402-406 THEMAINOBJECTIVEOFNEU- Inthisarticle,weevaluatetheexperi-
role of brimonidine in optic nerve injury.
We also discuss the inability thus far to neuroprotective, an agent must meet thefollowing 4 criteria: (1) receptors on its tar- METHOD OF LITERATURE SEARCH
get tissues such as the optic nerve or retina,(2) adequate penetration into the vitre- References for this study were obtained by run- ous and retina at pharmacologic levels, (3) ning a search of the PubMed database (using induction of intracellular changes that en- the keywords brimonidine, neuroprotection, is- hance neuronal resistance to insult or in- chemic optic neuropathy, and ␣-2 adrenergic ago- nists). Approximately 55 references were ini- tially identified. References that addressed atleast 1 of 4 criteria for neuroprotection were included in this article. We did not include ref- erences focusing on glaucomatous or ocular hy- pertension-induced injury, as it is difficult to gan, Inc, Irvine, California) is a highly se- extrapolate the neuroprotective effects of bri- lective ␣2-adrenergic agonist that was in- monidine independent of its role in reducing troduced in 1996. During the past decade, brimonidine has gained attention for itsrole in reducing intraocular pressure in the RECEPTORS ON TARGET TISSUES
initial and long-term treatment of ocularhypertension and glaucoma.6 Although Without specific receptors on retinal gan- Author Affiliations:
glion cells, a neuroprotective agent can- safety and efficacy in lowering intraocu- not bind to its target tissue. Brimonidine lar pressure, more recent experimental and is a highly selective ␣2-adrenergic ago- nist with weak ␣1 activity.10 Several ani- mal studies3,11-15 demonstrated the pres- tions indicate that it might have therapeu- ence of ␣2 receptors in the retina or optic tic effects if used clinically to treat optic nerve head, laying the foundation for the (REPRINTED) ARCH OPHTHALMOL / VOL 127 (NO. 4), APR 2009 2009 American Medical Association. All rights reserved.
monidine. Immunohistochemistry has shown that ␣2A re- for 4 to 14 days before testing yields brimonidine con- ceptors reside within the ganglion cell layer and possi- centrations in the vitreous well above the level neces- bly within the inner nuclear layer and amacrine cells in sary to activate ␣2 receptors in the retina.2 Twelve hours rats.3 Rabbit eyes express 3 subtypes of ␣2 receptors,16 as after the last dosing, the mean (SD) brimonidine con- do monkeys and humans.17 Radioligand-binding mod- centration among 5 patients with pseudophakia was 14.9 els similarly documented the existence of ␣2 receptors (8.1) nM2. The overall mean brimonidine concentra- in porcine and bovine retinas11,12 and in human reti- tion in this study was 185 nM2. Results of animal stud- nas18; however, studies have yet to prove the presence ies suggest that brimonidine binds to melanin10 and main- of these receptors in the human optic nerve head.
tains its peak concentration in the ciliary body for 6 hours When ␣2-receptor agonists clonidine and xylazine are after a single dose.26 This may explain the significant vit- administered, they specifically increase the activation of real concentrations detected at 10 to 14 hours after the the extracellular-regulated kinase pathway in Müller cells last dose in humans.2 These findings indicate that topi- in the retina19 and inhibit cyclic adenosine monophos- cally applied brimonidine reaches adequate intraocular phate production.20 Endogenous ligands modulate dopa- concentrations for neuroprotection to be possible.
mine-containing neurons in the retina via these ␣2 re-ceptors.21 Findings from Hadjiconstantinou et al21 and ENHANCEMENT OF NEURONAL RESISTANCE
other evidence demonstrate that these ␣2 receptors are TO INSULT AND INTERRUPTION OF APOPTOSIS
able to bind endogenous ligands and specific ␣2-receptor agonists and antagonists and that this binding Experimental models suggest that brimonidine confers neu- exerts measurable effects in the treated retinas.
roprotection in several types of ocular injury, including is- Treating the retina with ␣2-adrenoreceptor agonists re- chemia-induced injury,1,24,27-30 optic nerve compression or sults in the attenuation of decreased compound action po- optic nerve crush injury,22,27,31 photoreceptor degenera- tential after optic nerve injury.22 Other experiments dem- tion,23 and ocular hypertension and glaucoma.5,6,32-34 We onstrated that ␣2 antagonists such as rauwolscine and will exclude discussion of glaucomatous or ocular hyper- yohimbine hydrochloride specifically impede the neuro- tension–induced injury, as it is difficult to extrapolate the protective effects of ␣2 agonists in models of optic nerve neuroprotective effects of brimonidine treatment indepen- and photoreceptor injury, respectively.22-24 This finding sug- dent of its role in reducing intraocular pressure.
gests that the receptors are present within the retina and Several experimental animal models demonstrated the that the activation of such receptors alters several signal- neuroprotective effects of topically and systemically ad- ing pathways in the retina. In addition, the activation of ministered brimonidine in reducing the effects of optic these receptors seems to have a role in neuroprotective ac- nerve injury, as measured by decreased apoptosis or en- tivity after optic nerve or retinal injury.
hanced retinal ganglion cell survival. Topical applica-tion of brimonidine 1 hour before partial optic nerve crush ADEQUATE PENETRATION INTO THE VITREOUS
or ischemic optic nerve injury in rats is effective in de- AND RETINA AT PHARMACOLOGIC LEVELS
creasing apoptosis in retinal ganglion cells, as indicatedby a large decrease in terminal deoxynucleotidyl trans- Brimonidine must adequately penetrate through the an- ferase–mediated biotin–deoxyuridine triphosphate nick- terior structural barriers of the eye, including the cor- end labeling (TUNEL) staining.27 After ischemic injury nea, conjunctiva, and sclera, to reach the posterior vit- caused by 60- or 90-minute ligation of the ophthalmic reous and retina at pharmacologic doses. Preclinical artery, systemic administration of brimonidine rescued investigations revealed that a minimum concentration of 26% to 33% of the retina ganglion cell population, while 2nM brimonidine is needed to activate ␣2 receptors, which topical administration prevented up to 55% of retinal gan- equates to 0.88 ng/mL.25 Animal findings demonstrated glion cell loss, allowing almost 100% survival of the reti- that the aqueous concentrations of brimonidine in al- nal ganglion cells.28 The effect of brimonidine treatment bino and pigmented rabbits after topical administration was shown to be dose dependent and ␣2-adrenergic re- ranges between 0.03 and 2.2 ng/mL during a 6-hour pe- riod after topical administration.26 After single and mul- Using the ophthalmic vessel ligation method of optic tiple dosing, topically applied brimonidine distributes into nerve ischemia, brimonidine was administered to rats 1 the posterior segment of monkey and rabbit eyes at con- hour before 90-minute ligation.29 This single dose of topi- centrations sufficient to activate ␣2 receptors. Specifi- cal or systemic brimonidine rescued 42% of retinal gan- cally, after multiple topical administrations of bri- glion cells 7 days after the induction of ischemia. This monidine tartrate (0.5% [5 mg/mL]) in monkey and rabbit neuroprotective effect persisted at 21 days, suggesting that eyes, the dose-normalized concentrations in the vitre- brimonidine treatment could be neuroprotective during ous were 82 nM and 172 nM, respectively. Intraperito- the second phase of apoptosis seen in these types of op- neal injection of brimonidine tartrate (0.5 mg/kg) in rats tic nerve injury.29 These findings were confirmed and ex- revealed parallel results; peak vitreal humor concentra- tended. In another study,36 topical pretreatment with bri- tion was 22 nM, and peak neuroretinal concentration monidine 1 hour before transient ligation of the reached 138 nM.10 Each of these concentrations ex- ophthalmic vessels in rats significantly protected against ceeds the 2-nM concentration required for ␣2-receptor ischemia-induced damage of the inner and outer nuclear activation within the target tissues.
layers morphometrically and functionally after 3 months.
Similarly, findings in humans showed that topical in- In addition, this brimonidine treatment prevented de- stillation of brimonidine tartrate (0.2%) 2 to 3 times daily generation of retinotectal projections. Eight-four per- (REPRINTED) ARCH OPHTHALMOL / VOL 127 (NO. 4), APR 2009 2009 American Medical Association. All rights reserved.
cent of the volume of retinotectal projections was pre- mic injury is exciting. Even in the absence of controlled served in the brimonidine-treated rats compared with 50% clinical trials, physicians prescribed brimonidine and ␣ in the rats that received ischemic optic nerve injury and agonists as treatment for NAION. This perhaps stems from the substantial experimental evidence demonstrating the The long-term neuroprotective activity of bri- efficacy of brimonidine as a neuroprotective agent in ani- monidine was examined when topically administered be- mal models of ischemia. However, the results of clinical fore and after ischemic insult produced by a photoco- investigations suggest that brimonidine treatment has agulopathy method.30 These data support that failed to meet the fourth and final criteria for neuropro- pretreatment topically with brimonidine 7 days before tection, namely, similar efficacy in human clinical trials.
photocoagulation-induced optic nerve ischemia in rats Two studies examined the effectiveness of bri- can prevent long-term (5 months) neuronal and axonal monidine as a treatment for NAION in humans, one ret- loss. A limited and variable degree of ganglion cell res- rospective43 and the other prospective.44 Both studies ex- cue resulted from treatment with topical brimonidine for amined the potential effectiveness of brimonidine treatment 14 days, starting after the ischemic insult. This con- given, on average, 1 week after the NAION attack and ex- trasts findings by Lafuente et al,28 who found that intra- amined alterations in visual acuity as their primary end peritoneal brimonidine administered 4, 24, or 72 hours point. Neither study demonstrated neuroprotective effi- after the onset of transient ischemia and reperfusion had cacy of brimonidine as found in experimental animal mod- no effect on retinal ganglion cell survival. Differences in els. Fazzone et al43 performed a retrospective study of 31 these 2 studies could be because of differing methods of patients with NAION evaluated within 3 weeks of the on- producing ischemia, various routes of brimonidine ad- set of visual loss. Fourteen patients received topical bri- ministration, varying time between reperfusion and the monidine tartrate up to 4 times daily within 14 days of the initiation of treatment, or differences in the duration of onset of visual loss, while the other 17 patients were de- mographically matched to the treatment group and served In a model of endothelin 1 (ET-1)–induced chronic as control subjects. No positive effects of brimonidine treat- ischemia, topical brimonidine tartrate had a primary effect ment were seen in this small group of patients. The au- on vasoconstriction and decreased ocular blood flow.1 En- thors reported a trend toward worse outcomes at 8 weeks’ dothelin 1 acts via the ETa and ETb receptors, which are follow-up in the brimonidine-treated group for visual fields, present in the retina, optic nerve, and optic nerve head color vision, and visual acuity testing. However, no statis- of rabbits and humans.37 Therefore, there is ample evi- tical differences were seen, suggesting that the power of the dence that after optic nerve injury produced by several study was low because of few patients and the lack of con- methods brimonidine treatment has the ability to be neu- trol over which patients received brimonidine treatment roprotective to the injured ganglion cells.
The exact mechanism of the role of brimonidine in A double-masked randomized placebo-controlled trial neuroprotection remains unclear. Several studies pro- assessing the efficacy and tolerability of brimonidine tar- posed possible mechanisms for the ability of the drug to trate (0.2%) for the treatment of NAION was under- prolong cellular survival and function and attenuate apop- taken.44 Unlike in the study by Fazzone et al,43 the re- tosis. For example, degeneration of optic nerves in rats sults did not indicate any negative effects of brimonidine leads to elevated intraocular levels of excitotoxins, in- use in patients with NAION. There seemed to be a slight cluding aspartate and glutamate.38 Activation of the ␣2- nonsignificant improvement in visual fields for the treat- adrenergic receptors by brimonidine reduced levels of in- ment group compared with the control group. No seri- travitreal glutamate secondary to ischemia in the rat.24 ous adverse effects or events were noted. Ultimately, the Several studies23,39-41 demonstrated that intravitreal ad- results were inconclusive, and a statistically significant ministration of brimonidine in rats results in elevated lev- advantage for the patients receiving brimonidine was not els of neurotrophic factors, including brain-derived neu- demonstrated. After unmasking the data, the investiga- rotrophic factor and fibroblast growth factor. In vitro and tors chose to halt the trial because of poor recruit- after intravitreal injection, these factors are important in ment.44 Again, treatment was begun within the first week preserving retinal ganglion cells after various forms of after visual loss but not immediately after the first sign injury.42 Activation of ␣2-selective adrenergic agonists by
brimonidine also has been shown to upregulate intrin- Studies involving other optic neuropathies such as sic cell survival signaling pathways and antiapoptotic genes Leber hereditary optic neuropathy reported similar un- such as Bcl-2 and BCL-XL.4 The neuroprotective proper- successful results in clinical trials. Topical treatment with ties of brimonidine are likely multifactorial.
brimonidine purite (0.15%) 4 times daily to the unaf-fected eye for up to 2 years did not prevent second eye EFFICACY OF NEUROPROTECTION
involvement in 9 patients with recently documented mon- IN CLINICAL TRIALS
ocular vision loss from Leber hereditary optic neuropa-thy.45 A recent prospective placebo-controlled, double- Despite the accumulation of medical literature regard- masked, randomized clinical trial of 17 patients with ing the various aspects of nonarteritic anterior ischemic retinal dystrophies also found no statistically significant optic neuropathy (NAION) and Leber hereditary optic results in favor of brimonidine treatment; however, a non- neuropathy in humans, little is understood about these significant trend was found, suggesting slower progres- diseases. NAION has no effective treatment; therefore, sion of visual field loss in eyes treated with topical bri- the potential of brimonidine for treatment of this ische- (REPRINTED) ARCH OPHTHALMOL / VOL 127 (NO. 4), APR 2009 2009 American Medical Association. All rights reserved.
Topical brimonidine exhibited a positive effect on re- CONCLUSIONS
ducing collateral damage caused by laser photocoagula-tion for choroidal neovascularization in a small human The literature confirms that brimonidine meets the fol- study.47 Contrary to the previously discussed trials, the lowing 3 criteria for neuroprotection: (1) receptors on patients received brimonidine before laser treatment and its target tissues such as the optic nerve or retina, (2) ad- for 1 month after laser treatment. This is consistent with equate penetration into the vitreous and retina at phar- previous findings of ischemia in rats showing that bri- macologic levels, and (3) induction of intracellular monidine treatment is most efficacious before the in- changes that enhance neuronal resistance to insults or jury.30 Nevertheless, clinical shortcomings such as small interrupt programmed cell death mechanisms (apopto- sample size and inconclusive results warrant further re- sis) in animal models. However, the achievements in ani- mal models regarding the neuroprotective effects of bri-monidine in treating ischemic optic nerve injury have nottranslated into effective clinical applications. The fourth WHY CLINICAL MODELS MAY HAVE FAILED
criterion, demonstration of similar efficacy in clinical trials,has yet to be met.
Several differences exist between the experimental and Ultimately, these differing data and the lack of effi- clinical models, as well as unique challenges when work- cacy in clinical applications warrant additional studies.
ing with human subjects. This may explain the failure Potential focuses for these studies include the follow- of clinical results, despite the successes of diverse ani- ing: the cellular and molecular differences between is- mal models in demonstrating the neuroprotective ef- chemia-induced optic nerve injury in animals vs hu- fects of brimonidine treatment. For instance, earlier treat- mans, the specific cellular and molecular mechanisms ment in the clinical trials may be required. The most underlying the neuroprotective activity of brimonidine, notable successes in experimental models involved groups a decrease in the time between disease onset and treat- in which treatment with brimonidine preceded the op- ment, and perhaps new modes of delivery of neuropro- tic nerve injury.30,47 However, the annual incidence of tective agents and neurotrophic factors.
NAION is 5 cases per 100 000. Among subjects who ex-perience an attack of NAION, 15% to 25% will experi- Submitted for Publication: August 28, 2008; final revi-
ence an attack in the fellow eye within the next 5 years.
sion received December 1, 2008; accepted December 8, Practically speaking, this precludes a large-scale trial using brimonidine before the ischemic injury. Other data in ani- Correspondence: Michael S. Lee, MD, Department of
mal models showed that posttreatment with bri- Ophthalmology, University of Minnesota, 420 Dela- monidine yields mild to moderate effects on ganglion cell ware St SE, Mayo Mail Code 493, Minneapolis, MN 55455 survival.30 These findings suggest that a window of time exists between the initial phases of injury and the final Financial Disclosure: None reported.
phases of cell death. During this time frame, posttreat- Funding/Support: This study was supported by an un-
ment with a neuroprotective agent could rescue injured restricted grant from Research to Prevent Blindness and neurons.1,28,30 Therefore, starting brimonidine treat- ment sooner after the ischemic event (hours rather thandays or weeks) might significantly increase its potentialtherapeutic effect. Increased dosing frequency or use of a different preparation of brimonidine may represent otheravenues for enhancing the effectiveness of treatment.
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(REPRINTED) ARCH OPHTHALMOL / VOL 127 (NO. 4), APR 2009 2009 American Medical Association. All rights reserved.
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(REPRINTED) ARCH OPHTHALMOL / VOL 127 (NO. 4), APR 2009 2009 American Medical Association. All rights reserved.

Source: http://www.lkmcloon.umn.edu/publications/2009/Arch%20Ophthalmol%202009%20Saylor%20et%20al.pdf


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