IOVS Journal Watch
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by WoldeMussie, E.
Right arrow Articles by Wheeler, L. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by WoldeMussie, E.
Right arrow Articles by Wheeler, L. A.
(Investigative Ophthalmology and Visual Science. 2001;42:2849-2855.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Neuroprotection of Retinal Ganglion Cells by Brimonidine in Rats with Laser-Induced Chronic Ocular Hypertension

Elizabeth WoldeMussie, Guadalupe Ruiz, Mercy Wijono and Larry A. Wheeler

From the Department of Biological Sciences, Allergan Inc., Irvine, California.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
PURPOSE. To examine the neuroprotective effect of the {alpha}2-adrenergic agonist brimonidine in a chronic ocular hypertension model.

METHODS. Intraocular pressure (IOP) was elevated by laser photocoagulation of episcleral and limbal veins. Retinal ganglion cell loss was evaluated in wholemounted retinas. Brimonidine or timolol was administered, either at the time of or 10 days after IOP elevation and continued for 3 weeks. Drug-related immunohistochemical changes in glial fibrillary acidic protein (GFAP) were also determined after 3 weeks.

RESULTS. Laser treatment caused a twofold IOP increase over baseline that was maintained for 2 months. A time-dependent loss of ganglion cells occurred with elevated IOP. Systemic administration of brimonidine or timolol caused little decrease in IOP. After 3 weeks of elevated IOP, ganglion cell loss in control rats was 33% ± 3%. Brimonidine reduced the progressive loss of ganglion cells to 26% ± 1% and 15% ± 2% at doses of 0.5 and 1 mg/kg · d, respectively. Timolol had no effect. Ten days of high IOP resulted in 22% ± 4% ganglion cell loss. Brimonidine administration initiated 10 days after IOP elevation prevented any further loss of ganglion cells. In vehicle- or timolol-treated rats, ganglion cell loss continued to 33%. The increase in immunoreactivity of GFAP in ocular hypertensive retinas was attenuated by brimonidine.

CONCLUSIONS. Systemic application of brimonidine or timolol had little effect on IOP. Brimonidine, but not timolol, showed significant protection of retinal ganglion cells when applied at the time of IOP elevation and prevented further cell loss when applied after IOP was elevated. This indicates that brimonidine has a neuroprotective activity unrelated to its effect on ocular hypotension.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Glaucoma-induced ganglion cell degeneration is one of the leading causes of blindness. One of the most well-defined risk factors of glaucomatous ganglion cell damage is chronic elevation of IOP. Recent reports have hypothesized possible mechanisms of this neurodegeneration. Increase in vitreal glutamate in humans with glaucoma and animals with experimental hypertension has suggested that glutamate excitotoxicity may be involved in glaucomatous retinal damage.1 Others have reported that reduction of transport of neurotrophic factors may be the cause of ganglion cell death.2 3 In these situations, apoptosis has been reported to be a process of ganglion cell death.4 Such reports shed light on the mechanisms of ganglion cell injury and suggest the need for a direct therapeutic approach to prevent cell damage or enhance survival.

The conventional treatment of glaucoma has been directed toward controlling IOP. One of the compounds that are currently used in the control of pressure for open-angle glaucoma is the {alpha}2-adrenergic receptor agonist brimonidine. It is very effective in lowering IOP. There is also evidence that {alpha}2-adrenergic agonists protect neurons from damage in several models of ischemia. For example dexmedetomidine has been reported to be protective in focal cerebral ischemia in rat and rabbit5 and in incomplete forebrain ischemia in rats.6 Brimonidine has also been shown to have neuroprotective activity in a variety of neuronal injury models, such as light-induced photoreceptor damage, optic nerve injury, and acute retinal ischemia.7 8 9 In the present study we established laser-induced chronic ocular hypertension in rats and used this model to investigate the neuroprotective effect of brimonidine. We compared the neuroprotective effect of brimonidine to that of timolol, another ocular hypotensive compound used in the treatment of glaucoma.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Elevation of IOP
Experiments were conducted in strict accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and strict adherence to internal animal care and use committee guidelines. Male Wistar rats weighing 350 to 450 g were used. IOP was elevated by laser photocoagulation with a blue-green argon laser (Coherent, Palo Alto, CA). Rats were anesthetized with a mixture of ketamine (50 mg/kg), acepromazine (1 mg/kg), and xylazine (25 mg/kg). Laser treatment was performed on the episcleral veins within 0.5 to 0.8 mm from the limbus and on the veins in the limbus. Treatment was applied in two parts, 1 week apart. The amount of energy used was 1 W for 0.2 seconds, delivering a total of 130 to 150 spots (50–100 µm spot size) with both laser treatments.

IOP was measured by tonometer (Tono-Pen; Mentor, Norwell, MA) as described previously, with some modification.10 Rats were injected with 3.0 mg/kg acepromazine intramuscularly, enough to keep them calm but not to sedate them. Proparacaine (0.5%) was applied topically on the eyes to anesthetize the cornea. Fifteen readings were taken and averaged to give one measurement. IOP measurements were taken three times for the first 2 weeks and then once a week for the remainder of the experimental period. In drug-treated rats, IOP was measured once a week. To determine the correlation of elevated IOP and ganglion cell loss, IOP was elevated for different periods ranging from 4 to 60 days, and ganglion cell loss was evaluated.

Drug Treatment
Drugs were administered continuously using an osmotic pump that was inserted subcutaneously on the back. They were administered in two different paradigms. In one group, brimonidine (0.5 or 1 mg/kg · d, n = 10), timolol (1 or 2 mg/kg · d, n = 10), or phosphate-buffered saline (PBS) vehicle (n = 10) was administered at the time of initial IOP elevation. Age-matched naïve control rats (n = 5) were used to determine baseline ganglion cell number. In another group, IOP was elevated for 10 days before drug treatment with 1 mg/kg · d brimonidine (n = 15) or 2 mg/kg · d timolol (n = 15), or PBS vehicle (n = 15). As before, an age-matched group (n = 9) was used to determine baseline. In both paradigms treatment was continued for 3 weeks after drug administration.

Because the drug treatment was continuous for 3 weeks, it was important to establish that the high dose of brimonidine did not cause sedation. To determine this, rats were treated with brimonidine at 1 mg/kg · d (n = 3) for 9 days, and locomotor activity was measured on days 5 and 9 and compared with that of vehicle-treated rats. Activity was measured in photocell cages where horizontal and vertical movements were recorded with an activity monitor (Digiscan Animal Activity Monitor; Omnitech Electronics, Columbus, OH). Locomotor activity was defined as the total number of horizontal and vertical beam interruptions over a 5-minute period.

Retinal Ganglion Cell Count
The effect of elevated IOP on retinal ganglion cell loss was examined histologically in wholemounted retinas. At the end of each experimental period, the ganglion cells were labeled by retrograde transport using crystals of 3000 molecular weight (MW) dextran tetramethylrhodamine (DTMR; Molecular Probes, Eugene, OR). This dye traveled by diffusion at the rapid rate of 2 mm/hour and did not require active transport.11 Thus, we assumed that all the ganglion cells would be labeled regardless of health, as long as they were present. Rats were deeply anesthetized and the optic nerve was exposed. A longitudinal incision was made on the meningis, and the optic nerve was completely sectioned at approximately 2 to 3 mm from the globe. Crystals of DTMR were applied to the cut end of the optic nerve. To determine whether IOP elevation impeded the transport of the dye, we compared effectiveness of labeling in normotensive eyes (n = 5), with eyes in which IOP was raised twofold by laser treatment for 1 day (n = 5). Twenty-four hours after application of DTMR, the rats were killed, eyes enucleated, and fixed with 4% paraformaldehyde. The retinas were wholemounted, and labeled ganglion cells in eight central (0.66–1.103 mm from the edge of the optic disc) and four to eight peripheral (1.98–2.43 mm) areas in four quadrants of the retina were counted under 400x magnification. These areas represent 2.34% to 3.12% of the ganglion cells in the retina. Non–laser-treated, age-matched retinas were counted in the same areas to estimate total ganglion cell number. Ganglion cell loss in experimental eyes was calculated as percentage of cell loss compared with the non–laser-treated control. Percentage protection of ganglion cells by test compounds was calculated by comparing to vehicle-treated rats.

Immunohistochemistry
We had shown that elevation of IOP resulted in increase in immunoreactivity of intermediate filament glial fibrillary acidic protein (GFAP) in Müller cells.12 In this study we examined whether treatment with brimonidine affects the increase in this protein. At the end of the experimental period, fixed retinas were cryoprotected with sucrose (10%–30%) at 4°C for 2 days. Cuts were made at the horizontal meridian, and retinas were frozen in optimal cutting temperature compound (OCT; Tissue Tek, Torrance, CA). Cross sections of 15 µm were made from the upper half of the retina, collected on gelatin-coated slides, and air dried. The sections were then rehydrated and incubated with 10% normal goat serum in PBS for 30 minutes to block nonspecific sites. The sections were incubated overnight with the primary antibody; polyclonal rabbit anti-cow GFAP (Dako, Carpinteria, CA) diluted at 1:500, at 4°C in a humidified chamber. The following day they were rinsed with PBS and incubated with biotinylated secondary antibody for 60 minutes followed by indocarbocyanine (Cy 2)-conjugated avidin (Jackson ImmunoResearch, West Grove, PA.), rinsed, and coverslipped. Control samples were incubated without primary antibodies. Quantitative analysis of the immunostaining was performed by measuring fluorescence intensity by computer (Image Pro software; Media Cybernetics, Silver Spring, MD) using the "count-measure" function. Several sections were made, and five to six samples (every five sections) were immunostained. Images from these sections from all the rats were captured on camera (Spot; Diagnostic Instruments Inc., Sterling Heights, MI), with the same magnification and exposure period on the same day, and stored in the computer for further processing. Using the same size of sampling area in different layers of the retina, fluorescence intensity was measured in pixels and the numbers recorded. The absolute intensity values were normalized to a mean value from non–laser-treated control retinas. The control value was expressed as 1. Changes in intensity in laser-treated eyes were calculated in relation to the normalized control.

Statistical Analysis
The data are expressed as mean ± SEM. Statistical comparison was made using unpaired Student’s t-test. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
IOP and Ganglion Cell Loss
Laser photocoagulation of limbal and episcleral veins performed close to the limbus resulted in increased IOP. The baseline IOP in acepromazine-treated non–laser-treated rats was 16 ± 0.4 mm Hg (n = 25). The first laser treatment increased IOP to 25 to 27 mm Hg, approximately 1.6-fold over baseline (Table 1) . The second laser treatment increased IOP to a maximum of approximately 32 to 35 mm Hg (approximately twofold). This level of IOP was sustained for longer than 2 months, with a slight decrease. Elevated IOP-induced ganglion cell loss was evaluated by labeling the ganglion cells with DTMR at the optic nerve 1 day before the end of each time point. To determine whether IOP elevation did not obstruct the transport of the dye, we compared quantity of labeling in normotensive eyes, with eyes in which IOP had been increased twofold for 1 day. At normal IOP of 16.4 ± 0.1 mm Hg, ganglion cell count was 1393 ± 47/mm2 (n = 5). At the high IOP of 30.2 ± 0.5 mm Hg, the number of cells was 1207 ± 73/mm2 (n = 5). These numbers were not significantly different from each other (P > 0.05), indicating that the transport of DTMR was not hindered by elevated IOP.


View this table:
[in this window]
[in a new window]
  		Table 1. Time Course of Laser-Induced Increase in IOP and Ganglion Cell Loss

 
Elevation of IOP by laser treatment caused a time-related loss of ganglion cells (Table 1) . The loss of ganglion cells was linear for the first 3 weeks, resulting in a calculated cell loss of 12% per week and slowed to 2% per week from 3 weeks to 2 months. The average cell loss over the 2-month period was at 5% per week. By examining the ganglion cell loss in the different quadrants, we noted a regional variation in which there were more cells lost in the superior half than in the inferior half (Table 2) . Although this difference was evident at all time points, it was significant after 1 and 2 months of elevated IOP only.


View this table:
[in this window]
[in a new window]
  		Table 2. Regional Variation of Ganglion Cell Loss after Elevation of IOP

 
Effect of Brimonidine or Timolol on IOP
The effect of timolol or brimonidine was evaluated after systemic administration. These drugs have side effects, such as slowing of the heart rate (timolol) and sedation and a decrease in blood pressure (brimonidine), when administered systemically. Sedation was a big concern, because it would interfere with the rats’ eating or drinking. Therefore, we tested the highest dose (1 mg/kg · d) of brimonidine for its sedative effect, using as a measure locomotor activity on days 5 and 9 after placing the osmotic pump. Total activity was 3360 ± 301 (vehicle) and 3159 ± 341 (brimonidine) on day 5 (P > 0.66) and 2177 ± 452 (vehicle) and 2511 ± 388 (brimonidine) on day 9 (P > 0.66). These values were not significantly different from each other, indicating that there was no side effect from this dose of brimonidine. In addition, these animals appeared active when routinely observed in their cages.

In the first treatment paradigm, the compounds were administered immediately after initial laser treatment. Systemic administration of either brimonidine or timolol lowered IOP very slightly by 5% to 10% at both doses tested (Fig. 1) . In the second treatment paradigm, in which drug treatment commenced 10 days after elevation of IOP, neither brimonidine nor timolol showed any effect on IOP (Fig. 2) .



View larger version (19K):
[in this window]
[in a new window]
  		Figure 1. Effect of systemically administered brimonidine or timolol on IOP. IOP was increased with laser treatment. Brimonidine (A) at 0.5 or 1 mg/kg · d or timolol (B) at 1 or 2 mg/kg · d was administered subcutaneously at the time of first laser treatment. Both drugs caused minimal effect on IOP. Non–laser-treated (unlasered) eyes had IOP of 15 mm Hg. Values represent mean ± SEM of measurements in 10 rats.

 


View larger version (21K):
[in this window]
[in a new window]
  		Figure 2. Brimonidine (1 mg/kg · d) or timolol (2 mg/kg · d) showed no effect on IOP when administered 10 days (arrow) after laser treatment. Values represent mean ± SEM from 15 rats.

 
Effect of Brimonidine or Timolol on Ganglion Cell Loss
After 3 weeks of elevated IOP, there was a considerable decrease in labeled ganglion cells in retinas of vehicle-treated eyes compared with those treated with brimonidine during the same period (Fig. 3) . The ganglion cell loss, in vehicle-treated rats was 33% after 3 weeks of elevated IOP (Fig. 4) . Brimonidine treatment during this 3-week period resulted in a dose-related protection of ganglion cells in which cell loss was reduced to 26% ± 1% and 16% ± 3% with 0.5- and 1-mg/kg · d doses, respectively (Fig. 4) . Timolol treatment did not have any protective effect with either dose (Fig. 4) .



View larger version (44K):
[in this window]
[in a new window]
  		Figure 3. Representative wholemounted retinas from hypertensive eyes labeled with DTMR, after treatment with vehicle (A) or brimonidine (B) for 3 weeks. There were more labeled cells in the brimonidine-treated retina than in the vehicle-treated one. Bar, 50 µm.

 


View larger version (17K):
[in this window]
[in a new window]
  		Figure 4. Neuroprotective effect of brimonidine or timolol on ganglion cells in hypertensive eyes. Brimonidine applied at the time of laser treatment and continued for 3 weeks caused a dose-related prevention of ganglion cell loss. This protection was significant with 1 mg/kg · d treatment (*P < 0.05). Timolol had no effect. Values represent mean ± SEM of measurements in 10 rats.

 
After 10 days of IOP elevation there was a 22% ± 4% decrease in ganglion cell number (Fig. 5) . Drug treatment was initiated at this time and continued for 3 weeks. Ganglion cell loss in brimonidine-treated rats remained at 22% ± 3.8%, whereas those treated with vehicle or timolol continued to 33% ± 5.6% or 35% ± 3.3%, respectively (Fig. 5) .



View larger version (18K):
[in this window]
[in a new window]
  		Figure 5. Brimonidine-induced neuroprotection of ganglion cells. Brimonidine at 1 mg/kg · d or timolol at 2 mg/kg · d was applied 10 days (arrow) after first laser treatment. There was a 22% decrease in ganglion cells after 10 days. Treatment with brimonidine prevented any further loss of ganglion cells (*P < 0.05). Timolol had no effect on ganglion cell loss. Values represent mean ± SEM of measurements in 15 rats.

 
Immunohistochemistry
In normal retina, GFAP immunoreactivity is restricted to astrocytes and end feet of the Müller cells at the inner limiting membrane. However, its expression increases after different types of retinal injury.12 13 14 After elevation of IOP, GFAP immunoreactivity increased throughout the length of the Müller cells (Fig. 6) . Treatment with brimonidine caused a significant decrease in GFAP expression compared with vehicle-treated eyes (Fig. 6) . This decrease spanned the length of the Müller cells (from ganglion cell to photoreceptor layers). Timolol did not show any decrease in immunoreactivity of GFAP.



View larger version (61K):
[in this window]
[in a new window]
  		Figure 6. Immunohistochemical staining of retinas for GFAP. Drugs were administered at the time of IOP elevation. Three weeks later, eyes were fixed and cross-sectioned retinas were stained with anti-GFAP antibody. (A) GFAP immunostaining in retinas with normal IOP was limited to the end feet of Müller cells in the fiber layer. (B) Elevation of IOP increased GFAP staining. (C) Brimonidine caused a significant decrease in GFAP staining (*P < 0.025). (D) Timolol caused a slight, nonsignificant decrease. (E) Quantitative analysis of fluorescence intensity of GFAP, measured in all layers of the retina. Values represent mean ± SEM of measurements in three retinas. RGC, retinal ganglion cells; IPL, inner plexiform layer; INL, inner nuclear layer; PR, photoreceptor.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Glaucoma-induced vision loss is the result of degeneration of ganglion cells and their axons. Although it is well established that elevated IOP is one of the risk factors in this disease process the mechanism of degeneration is unclear. The continued loss of vision in eyes with glaucoma, despite control of IOP, emphasizes the need for neuroprotective therapy. The development of a chronic ocular hypertension model in the rat provides a valuable means of evaluating the mechanism and process of injury and can be used to evaluate compounds with neuroprotective activity.4 10 15 16 17 18 In this study, the neuroprotective effect of brimonidine was examined using rats with laser-induced chronic ocular hypertension. All the rat models reported by others and the one described in this study have shown that elevation of IOP causes ganglion cell or optic nerve fiber loss.4 10 15 16 17 18 It has also been shown that the level of IOP obtained determines the extent of ganglion cell loss.4 In this study, IOP elevation of twofold caused ganglion cell loss of 44% after 2 months, averaging 5.5% per week. This result is comparable to previous reports showing that cell losses of approximately 37% and 47% were obtained after 6 and 10 weeks, averaging 6% and 5% per week, respectively.4 15 Other investigators have observed cell loss at a slower rate of 1.4% per week when the average cell loss was calculated over a longer period of 6 months and the increase in IOP was 1.6-fold or less.17 We noted a biphasic rate of ganglion cell loss with a fast rate of 12% per week for the first 3 weeks of IOP elevation, followed by a slower rate of 2% per week for the remainder of the experimental period. The rate of ganglion cell loss in the other studies is linear.4 15 17

In prior studies cautery was used once to occlude two or three major episcleral veins, 2 to 3 mm from the limbus, whereas laser treatment in the present study was performed twice, on several veins within 1 mm from the limbus. Thus, in addition to a difference in the technique of vessel occlusion, the discrepancy in rate of ganglion cell loss could also be due to the rate at which the target IOP was reached and maintained. In this study, target IOP was reached by two laser treatments within 1 week, which may have initiated a faster rate of initial ganglion cell loss. The consistent and significant loss of ganglion cells after 3 weeks of elevated IOP provided us with an opportunity to evaluate neuroprotective activity of pharmacologic agents within a relatively short period.

In this study, we provide evidence that the {alpha}2-adrenergic agonist brimonidine is neuroprotective of ganglion cells in eyes with laser-induced chronic ocular hypertension. Brimonidine is currently used to lower IOP in the treatment of open-angle glaucoma.19 20 21 The neuroprotective effect of brimonidine was evaluated in two different ways. When brimonidine was applied at the time of IOP elevation, before pressure-induced ganglion cell injury began, it attenuated ganglion cell loss by 50% (cell loss with vehicle 33% and with brimonidine 15%), in spite of the sustained increase in IOP. More interesting was that when brimonidine was administered 10 days after IOP was elevated, it prevented any further loss of ganglion cells. In both treatment paradigms systemically applied brimonidine (400 µg/d or 17 µg/h to each rat) reached the retina in sufficient amount to exert neuroprotection but had little or no effect on IOP. However, topically applied brimonidine (0.2%, 10 µg/5 µl) was effective in lowering IOP by 40% (data not shown) and was neuroprotective of retinal neurons in a rat acute retinal ischemia–reperfusion injury model.22 Moreover a recent study has shown that vitreal levels of brimonidine after topical application of a 0.2% dose in phakic eyes with planned vitrectomy was 9.3 ± 8 nM.23 This concentration is more than adequate to activate the {alpha}2 receptors in the retina. The median effective dose (EC50) of brimonidine for activating {alpha}2 receptors is approximately 2 nM.24

The neuroprotective effect of brimonidine was compared with that of timolol. Both brimonidine and timolol are currently used for the treatment of glaucoma, and they lower IOP significantly. It is thought that lowering of IOP reduces injury and preserves the visual field. In this study, brimonidine, but not timolol, was neuroprotective. Similar to brimonidine, topical timolol (0.5%, 5 µl) caused a decrease in IOP by 27% (data not shown). Similarly, the amount of timolol that reached the eye when delivered by osmotic pump appeared to be lower than required to decrease IOP. This emphasizes the direct neuroprotective effect of brimonidine.

In several models of retinal injury, stress, or degeneration, expression of GFAP increases in Müller cells.13 25 26 The increase in immunoreactivity of GFAP in this ocular hypertension model may be a response to the stress and pathologic process that leads to degeneration of ganglion cells. The decrease in GFAP immunoreactivity by brimonidine suggests that activation of the selective {alpha}2-adrenergic receptors reduces this injury in the retina.

Several mechanisms underlying the neuroprotective activity of {alpha}2-adrenergic agonists have been proposed. Brimonidine has been shown to increase neurotrophic factors7 and thus may be neuroprotective by enhancing the survival of ganglion cells in this hostile environment. In addition, activation of presynaptic {alpha}2-receptors results in inhibition of transmitter release.27 28 It is possible that brimonidine treatment attenuated the release of glutamate in the eyes with elevated IOP. Increase in vitreal glutamate has been implicated in excitotoxicity of ganglion cells in glaucoma.29 Although we did not measure vitreal glutamate in this study, there is a report showing that that brimonidine inhibits accumulation of glutamate in the vitreous after acute retinal ischemia.9

In summary, we have shown that laser photocoagulation of limbal and episcleral veins in the rat caused chronically elevated IOP, resulting in significant loss of ganglion cells. Systemic treatment with the {alpha}2 agonist brimonidine provided neuroprotection to ganglion cells in this model.


   Acknowledgements
 
The authors thank James Burke and Peter Baciu for critical comments on the manuscript.


   Footnotes
 
Supported by Allergan, Inc, Irvine, CA.

Submitted for publication January 3, 2001; revised May 21, and July 13, 2001; accepted August 2, 2001.

Commercial relationships policy: E.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Elizabeth WoldeMussie, Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612-1599. woldemussie_liz{at}allergan.com


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Dreyer, EB, Zurakowski, D, Schumer, RA, Podos, SM, Lipton, SA (1996) Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma Arch Ophthalmol 114,299-305[Abstract/Free Full Text]
  2. Quigley, HA (1999) Neuronal death in glaucoma Prog Retinal Eye Res 18,39-57[Medline][Order article via Infotrieve]
  3. Pease, ME, McKinnon, SJ, Quigley, HA, Kerrigan-Baumrind, LA, Zack, DJ (2000) Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma Invest Ophthalmol Vis Sci 41,764-774[Abstract/Free Full Text]
  4. Garcia-Valenzuela, E, Shareef, S, Walsh, J, Sharma, S. (1995) Programmed cell death of retinal ganglion cells during experimental glaucoma Exp Eye Res 61,33-44[Medline][Order article via Infotrieve]
  5. Maier, C, Steinberg, G, Sun, G, Zhi, G, Maze, M. (1993) Neuroprotection by the alpha-2-adrenegic agonist dexmedetomidine in a focal model of cerebral ischemia Anesthesiology 79,306-312[Medline][Order article via Infotrieve]
  6. Hoffman, W, Kochs, E, Werner, C, Thomas, C, Albrecht, R. (1991) Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha-2-adrenergic antagonist atipamezole Anesthesiology 75,328-332[Medline][Order article via Infotrieve]
  7. Wen, R, Cheng, T, Li, Y, Cao, W, Steinberg, R. (1996) 2-Adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage J Neurosci 16,5986-5992[Abstract/Free Full Text]
  8. Yoles, E, Wheeler, L, Schwartz, M. (1999) {alpha}2-Adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration (published correction appears in Invest Ophthalmol Vis Sci. 1999;40:2470) Invest Ophthalmol Vis Sci 40,65-73[Abstract/Free Full Text]
  9. Donello, J, Padillo, E, Webster, M, Wheeler, L, Gil, D. (2001) Alpha-2 adrenoceptor agonists preserve retinal function following transient ischemia by inhibiting vitreal glutamate and aspartate accumulation J Pharmacol Exp Ther 296,216-223[Abstract/Free Full Text]
  10. Morrison, J, Moore, C, Deppmeier, L, Gold, B, Meshul, C, Johnson, E. (1997) A rat model of chronic pressure-induced optic nerve damage Exp Eye Res 64,85-96[Medline][Order article via Infotrieve]
  11. Fritzsch, B. (1993) Fast axonal diffusion of 3000 molecular weight dextran amines J Neurosci Methods 50,95-103[Medline][Order article via Infotrieve]
  12. Wijono, M, WoldeMussie, E, Ruiz, G. (1999) Process of retinal ganglion cell damage by elevated intraocular pressure in rat eyes [ARVO abstract] Invest Ophthalmol Vis Sci 40(4),S672Abstract nr 3545
  13. Miller, DB, Blackman, CF, O’Callaghan, JP (1987) An increase in glial fibrillary acidic protein follows brain hyperthermia in rats Brain Res 415,371-374[Medline][Order article via Infotrieve]
  14. Vijayan, VK, Lee, YL, Eng, LF (1990) Increase in glial fibrillary acidic protein following neural trauma Mol Chem Neuropathol 13,107-118[Medline][Order article via Infotrieve]
  15. Laquis, S, Chaudhary, P, Sharma, S. (1998) The patterns of retinal ganglion cell death in hypertensive eyes Brain Res 784,100-104[Medline][Order article via Infotrieve]
  16. Ueda, J, Sawaguchi, S, Hanyu, T, Yaoeda, K, Fukuchi, T, Abe, H, Ozawa, H. (1998) Experimental glaucoma model in the rat induced by laser trabecular photocoagulation after an intracameral injection of India ink Jpn J Ophthalmol 42,337-344[Medline][Order article via Infotrieve]
  17. Sawada, A, Neufeld, A. (1999) Confirmation of the rat model of chronic moderately elevated intraocular pressure Exp Eye Res 69,525-531[Medline][Order article via Infotrieve]
  18. Mittag, TW, Danias, J, Pohorenec, G, et al (2000) Retinal damage after 3 to 4 months of elevated intraocular pressure in a rat glaucoma model Invest Ophthalmol Vis Sci 41,3451-3459[Abstract/Free Full Text]
  19. Adkins, JC, Balfour, JA (1998) Brimonidine: a review of its pharmacological properties and clinical potential in the management of open-angle glaucoma and ocular hypertension Drugs Aging 12,225-241[Medline][Order article via Infotrieve]
  20. Schuman, JS, Horwitz, B, Choplin, NT, David, R, Albracht, D, Chen, K. (1997) A 1-year study of brimonidine twice daily in glaucoma and ocular hypertension: a controlled, randomized, multicenter clinical trial. Chronic Brimonidine Study Group (see comments) Arch Ophthalmol 115,847-852[Abstract/Free Full Text]
  21. Serle, JB (1996) A comparison of the safety and efficacy of twice daily brimonidine 0.2% versus betaxolol 0.25% in subjects with elevated intraocular pressure. The Brimonidine Study Group III Surv Ophthalmol 41,S39-S47
  22. Wheeler, LA, Lai, R, WoldeMussie, E. (1999) From the lab to the clinic: activation of an alpha-2 agonist pathway is neuroprotective in models of retinal and optic nerve injury Eur J Ophthalmol 1(suppl),S17-S21
  23. Kent, AR, Nussdorf, JD, David, R, Tyson, F, Small, D, Fellows, D. (2001) Vitreous concentration of topically applied brimonidine tartrate 0.2% Ophthalmology 108,784-747[Medline][Order article via Infotrieve]
  24. Burke, J, Manlapaz, C, Kharlamb, A, et al (1996) Therapeutic Use of {alpha}2-Adrenoceptor Agonists in Glaucoma Lanier, SM Limbird, LE eds. {alpha}2-Adrenergic Receptors Structure, Function and Therapeutic Implications ,179-187 Harwood Academic Publishers Reading, UK.
  25. Erickson, P, Fisher, S, Guerin, C, Anderson, D, Kaska, D. (1987) Glial fibrillary acidic protein increases in Muller cells after retinal detachment Exp Eye Res 44,37-48[Medline][Order article via Infotrieve]
  26. Tanihara, H, Hangai, M, Sawaguchi, S, et al (1997) Up-regulation of glial fibrillary acidic protein in the retina of primate eyes with experimental glaucoma Arch Ophthalmol 115,752-756[Abstract/Free Full Text]
  27. Starke, K. (1977) Regulation of noradrenaline release by presynaptic receptor systems Rev Physiol Biochem Pharmacol 77,1-124[Medline][Order article via Infotrieve]
  28. Osborne, NN (1991) Inhibition of cAMP production by alpha 2-adrenoceptor stimulation in rabbit retina Brain Res 553,84-88[Medline][Order article via Infotrieve]
  29. Dreyer, E, Grosskreutz, C. (1997) Excitatory mechanisms in retinal ganglion cell death in primary open angle glaucoma (POAG) Clin Neurosci 4,270-273[Medline][Order article via Infotrieve]



This article has been cited by other articles:


Home page
 IOVSHome page
M. E. Pease, D. J. Zack, C. Berlinicke, K. Bloom, F. Cone, Y. Wang, R. L. Klein, W. W. Hauswirth, and H. A. Quigley
Effect of CNTF on Retinal Ganglion Cell Survival in Experimental Glaucoma
Invest. Ophthalmol. Vis. Sci., May 1, 2009; 50(5): 2194 - 2200.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
M. Saylor, L. K. McLoon, A. R. Harrison, and M. S. Lee
Experimental and Clinical Evidence for Brimonidine as an Optic Nerve and Retinal Neuroprotective Agent: An Evidence-Based Review
Arch Ophthalmol, April 1, 2009; 127(4): 402 - 406.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
C.-J. Dong, Y. Guo, P. Agey, L. Wheeler, and W. A. Hare
{alpha}2 Adrenergic Modulation of NMDA Receptor Function as a Major Mechanism of RGC Protection in Experimental Glaucoma and Retinal Excitotoxicity
Invest. Ophthalmol. Vis. Sci., October 1, 2008; 49(10): 4515 - 4522.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
Q.-L. Fu, B. Hu, W. Wu, R. B. Pepinsky, S. Mi, and K.-F. So
Blocking LINGO-1 Function Promotes Retinal Ganglion Cell Survival Following Ocular Hypertension and Optic Nerve Transection
Invest. Ophthalmol. Vis. Sci., March 1, 2008; 49(3): 975 - 985.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
J. Kusari, S. Zhou, E. Padillo, K. G. Clarke, and D. W. Gil
Effect of Memantine on Neuroretinal Function and Retinal Vascular Changes of Streptozotocin-Induced Diabetic Rats
Invest. Ophthalmol. Vis. Sci., November 1, 2007; 48(11): 5152 - 5159.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
S. Bakalash, A. Rolls, O. Lider, and M. Schwartz
Chondroitin Sulfate-Derived Disaccharide Protects Retinal Cells from Elevated Intraocular Pressure in Aged and Immunocompromised Rats
Invest. Ophthalmol. Vis. Sci., March 1, 2007; 48(3): 1181 - 1190.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
C.-J. Dong, Y. Guo, L. Wheeler, and W. A. Hare
{alpha}2 Adrenergic Receptor-Mediated Modulation of Cytosolic Ca++ Signals at the Inner Plexiform Layer of the Rat Retina
Invest. Ophthalmol. Vis. Sci., March 1, 2007; 48(3): 1410 - 1415.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
A T Fung, S E Reid, M P Jones, P R Healey, P J McCluskey, and J C Craig
Meta-analysis of randomised controlled trials comparing latanoprost with brimonidine in the treatment of open-angle glaucoma, ocular hypertension or normal-tension glaucoma
Br. J. Ophthalmol., January 1, 2007; 91(1): 62 - 68.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
R. K. P. Sullivan, E. WoldeMussie, L. Macnab, G. Ruiz, and D. V. Pow
Evoked Expression of the Glutamate Transporter GLT-1c in Retinal Ganglion Cells in Human Glaucoma and in a Rat Model.
Invest. Ophthalmol. Vis. Sci., September 1, 2006; 47(9): 3853 - 3859.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
R. S. Li, B.-Y. Chen, D. K. Tay, H. H. L. Chan, M.-L. Pu, and K.-F. So
Melanopsin-expressing retinal ganglion cells are more injury-resistant in a chronic ocular hypertension model.
Invest. Ophthalmol. Vis. Sci., July 1, 2006; 47(7): 2951 - 2958.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
W.-H. Wang, J. C. Millar, I.-H. Pang, M. B. Wax, and A. F. Clark
Noninvasive Measurement of Rodent Intraocular Pressure with a Rebound Tonometer
Invest. Ophthalmol. Vis. Sci., December 1, 2005; 46(12): 4617 - 4621.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
S. Mayor-Torroglosa, P. De la Villa, M. E. Rodriguez, M. P. L. Lopez-Herrera, M. Aviles-Trigueros, A. Garcia-Aviles, J. Miralles de Imperial, M. P. Villegas-Perez, and M. Vidal-Sanz
Ischemia Results 3 Months Later in Altered ERG, Degeneration of Inner Layers, and Deafferented Tectum: Neuroprotection with Brimonidine
Invest. Ophthalmol. Vis. Sci., October 1, 2005; 46(10): 3825 - 3835.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
F B Kalapesi, M T Coroneo, and M A Hill
Human ganglion cells express the alpha-2 adrenergic receptor: relevance to neuroprotection
Br. J. Ophthalmol., June 1, 2005; 89(6): 758 - 763.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
L. Guo, S. E. Moss, R. A. Alexander, R. R. Ali, F. W. Fitzke, and M. F. Cordeiro
Retinal Ganglion Cell Apoptosis in Glaucoma Is Related to Intraocular Pressure and IOP-Induced Effects on Extracellular Matrix
Invest. Ophthalmol. Vis. Sci., January 1, 2005; 46(1): 175 - 182.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
B. V. Bui, B. Edmunds, G. A. Cioffi, and B. Fortune
The Gradient of Retinal Functional Changes during Acute Intraocular Pressure Elevation
Invest. Ophthalmol. Vis. Sci., January 1, 2005; 46(1): 202 - 213.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. F. Cordeiro, L. Guo, V. Luong, G. Harding, W. Wang, H. E. Jones, S. E. Moss, A. M. Sillito, and F. W. Fitzke
Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration
PNAS, September 7, 2004; 101(36): 13352 - 13356.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
B. C. Chauhan, T. L. LeVatte, C. A. Jollimore, P. K. Yu, H. A. Reitsamer, M. E. M. Kelly, D.-Y. Yu, F. Tremblay, and M. L. Archibald
Model of Endothelin-1-Induced Chronic Optic Neuropathy in Rat
Invest. Ophthalmol. Vis. Sci., January 1, 2004; 45(1): 144 - 152.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
T Aung, F T S Oen, H-T Wong, Y-H Chan, B-K Khoo, Y-P Liu, C-L Ho, J See, L H Thean, A C Viswanathan, et al.
Randomised controlled trial comparing the effect of brimonidine and timolol on visual field loss after acute primary angle closure
Br. J. Ophthalmol., January 1, 2004; 88(1): 88 - 94.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
D W Evans, S L Hosking, D Gherghel, and J D Bartlett
Contrast sensitivity improves after brimonidine therapy in primary open angle glaucoma: a case for neuroprotection
Br. J. Ophthalmol., December 1, 2003; 87(12): 1463 - 1465.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
H E Fazzone, M J Kupersmith, and J Leibmann
Does topical brimonidine tartrate help NAION?
Br. J. Ophthalmol., September 1, 2003; 87(9): 1193 - 1194.
[Full Text] [PDF]

Home page
 IOVSHome page
B. C. Chauhan, J. Pan, M. L. Archibald, T. L. LeVatte, M. E. M. Kelly, and F. Tremblay
Effect of Intraocular Pressure on Optic Disc Topography, Electroretinography, and Axonal Loss in a Chronic Pressure-Induced Rat Model of Optic Nerve Damage
Invest. Ophthalmol. Vis. Sci., September 1, 2002; 43(9): 2969 - 2976.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
D. C. Baptiste, A. T. E. Hartwick, C. A. B. Jollimore, W. H. Baldridge, B. C. Chauhan, F. Tremblay, and M. E. M. Kelly
Comparison of the Neuroprotective Effects of Adrenoceptor Drugs in Retinal Cell Culture and Intact Retina
Invest. Ophthalmol. Vis. Sci., August 1, 2002; 43(8): 2666 - 2676.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by WoldeMussie, E.
Right arrow Articles by Wheeler, L. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by WoldeMussie, E.
Right arrow Articles by Wheeler, L. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS