A Fixed Combination of Brimonidine and Timolol (CombiganTM) Lowers Intraocular Pressure (IOP) and Reduces Retinal Ganglion Cell (RGC) Loss in the Rat Model of Ocular Hypertension

Abstract

Purpose:: Brimonidine has been reported to be neuroprotective (i.e. protects RGCs) in animal models of ocular hypertension and optic nerve injury (E. WoldeMussie, Minerva Oftalmol 2000:42). This study evaluated a fixed combination of brimonidine 0.2% and timolol 0.5% (Combigan^TM) on IOP and RGC survival in the laser-induced rat glaucoma model.

Methods:: Thirty Wistar rats were divided into five groups of six and laser-treated in OD for induction of OHT, as previously described (WoldeMussie et al IOVS, 2001 Vol. 42) with two laser sessions on Day 1 and Day 7. The five treatment groups were: naïve, PBS, brimonidine 0.2%, timolol 0.5%, and Combigan^TM. Animals were dosed with topical eye-drops (5 µL, BID) which began immediately after the 1^st laser treatment and continued for the 21 day study. At the end of the study, RGCs were labeled by retrograde transport using crystals of 3000 MW dextran tetramethylrhodamine (DTMR; Molecular Probes). The animals were euthanized 24 hours after labeling, eyes collected and fixed in 4% paraformaldehyde. Retinas were whole-mounted and labeled-RGCs were counted under fluorescent light with Rhodamine filters at 400X magnification. Data are presented as mean (SEM).

Results:: One week after the second laser treatment (Day 14), IOP increased two-fold to 30.7 ± 0.7 mm Hg and this pressure remained through Day 21 in the PBS-treated animals. All three actives prevented the rise in IOP with the following ranked order of potency at Day 21: Combigan > brimonidine > timolol. RGC decreased in the PBS-treated animals by 34.3 ± 1.2 %, compared to the naïve untreated eyes. Timolol, brimonidine and Combigan^TM decreased RGC counts by 24.3% ± 4.4%, 13 ± 1.9% and 9.1 ± 3.9%, respectively. The RGC responses in the brimonidine and Combigan^TM groups were significantly different (p<0.01) from the PBS-treated animals.

Conclusions:: Topical administration of a fixed combination of brimonidine and timolol decreased IOP, and was neuroprotective in a rat model of ocular hypertension.

Keywords: intraocular pressure • neuroprotection • ganglion cells