Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension.
OBJECTIVE
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.
WoldeMussie
E
E
Department of Biological Sciences, Allergan Inc., Irvine, California 92612-1599, USA. woldemussie_liz@allergan.com
Ruiz
G
G
Wijono
M
M
Wheeler
L A
LA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D002470:Cell Survival / Q000187:drug effects; D002908:Chronic Disease; D019610:Cytoprotection / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects*; D017075:Laser Coagulation / Q000009:adverse effects*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D013997:Time Factors; D013999:Timolol / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D011810:Quinoxalines; D000068438:Brimonidine Tartrate; D013999:Timolol