Abstract
Purpose :
To evaluate the ocular hypotensive effect and the neuroprotective efficacy of the topical synthetic CB1 receptor (CB1R) agonist, WIN 55,212-2, in a prospective, controlled preclinical study assessing intraocular pressure (IOP) and retinal ganglion cell function (pattern electroretinogram) variations in the DBA/2J (D2) mouse model of chronic glaucoma.
Methods :
Ninety 6-month-old D2 mice (M:F = 1:1) were randomized into three groups: 30 mice not receiving any treatment for the entire length of the study (Control), 30 mice treated with 1% WIN 55-212,2 and SR141716 2.7 mM (selective CB1R antagonist) eyedrops once a day from inception (Rimonabant), and 30 mice treated with 1% WIN 55-212,2 eyedrops once a day from inception (WIN-T0). WIN 55-212,2 and SR141716 were dissolved in a solution of balanced salt ophthalmic solution and a derivative of castor oil and ethylene oxide. Pattern electroretinogram (PERG) and IOP were measured from each eye every 2 months and up to 10 month-age under ketamine/xylazine anesthesia. Longitudinal data were analyzed using Generalized Estimating Equations (GEE) statistics.
Results :
No local side effects were noted during chronic topical therapy with either drug or the combination of agonist/antagonist. Figure 1 shows a steady, age-related decline of PERG amplitude in both the Control and the Rimonabant groups, with only minimal changes in the WIN-T0 group (Effect of Group, p < 0.0001; Control vs. WIN-T0, p <0.0001; Rimonabant vs. WIN-T0, p < 0.0001; Control vs. Rimonabant, p = 0.8). Age-related variations were also noted in the IOP, with statistically significant differences (p < 0.001) among groups (Effect of Group, p < 0.0001; Control vs. WIN-T0, p < 0.0001; Rimonabant vs. WIN-T0, p < 0.0001; Control vs. Rimonabant, p = 0.4). GEE analysis of PERG amplitude changes including IOP as covariate revealed the latter to exert a major impact on the statistical model (p < 0.0001).
Conclusions :
In the D2 model of chronic glaucoma, prolonged treatment with topical WIN 55-212,2 is able to exert a sustained ocular hypotensive effect and a significant neuroprotection on RGC function in a CB1R-dependent fashion and without the development of tolerance.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.