Purpose:
Glaucomatous damage to the retina and optic nerve progresses even after therapy to maintain normal intraocular pressure (IOP). Topical application of endogenous cannabinoid analogs decreases IOP in a rat model of glaucoma. Based upon their effects on other tissues, we hypothesize that these analogs may also confer direct neuroprotective effects on the retina, possibly via CB1 and/or CB2 receptors. The purpose of this study is to determine if these novel CB agonists, lipid soluble O–1812 (CB1> 2), and water soluble O–2545 (CB 1, 2) confer retinal neuroprotection.
Methods:
Retinal damage was induced by intravitreal injection of NMDA (2 µl of 10 mM) in Sprague–Dawley rats. In other groups 2 µl O–1812 (2 mM) or 2 µl O–2545 (2mM) were co–injected with NMDA. Electroretinograms (ERG) were recorded at baseline, 1 wk and 2 wk after injection. Contralateral normal eyes served as controls. After 2 wk, retinas were flat mounted and stained with H&E. In other experiments, IOP was obtained following topically applied O–1812 or O–2545.
Results:
At 1 wk, a–wave amplitude in all treatments was depressed with no functional change in b–wave. O–1812 was most effective in restricting functional loss of a–wave amplitude. At 2 wk, a–wave amplitudes improved only in drug treated group. O–1812 most effectively restored a–wave amplitude towards baseline; O–2545 was less effective. The a–wave amplitude in NMDA treated group continued to decline with the damage extending to b–wave amplitude. Both drugs significantly reduced IOP by 79 % 30 min after O–1812; by 78 % 60 min after O–2545 (p<0.05). Retinal whole mounts after NMDA alone showed areas devoid of cells, while those treated with O–1812 and O–2545 were intact with an even distribution of retinal ganglionic cells.
Conclusions:
Both compounds partially preserved functional a–waves, completely prevented b–wave loss, and maintained a normal distribution of ganglionic cells. Considering both IOP and neuroprotective effects, lipid soluble O–1812 was most effective.
Keywords: electroretinography: non-clinical • neuroprotection • drug toxicity/drug effects