VSN16S, an agonist of the cannabinoid receptor, reduces IOP profiles and exhibits neuroprotective properties in a rat model of glaucoma

Abstract

AbstractPurposeThere is an unmet need for new drugs in glaucoma that can effectively prevent glaucoma progression. We assessed the effects of VSN16S and AG‐020, the agonists of the cannabinoid receptor, on intraocular pressure (IOP) and neuroprotection using a rat model of ocular hypertension (OHT).Methods20 male Dark Agouti (DA) rats aged 8–10 weeks were randomly located into 4 groups (n = 5): OHT‐only, OHT+vehicle, OHT+VSN16S, and OHT+AG‐020. All animals had IOP surgically elevated in the left eye (OS) by injection of hypertonic saline into the episcleral veins. Except for OHT‐only, animals in the other 3 groups have received eye drops in OS either vehicle or VSN16S or AG‐0202 at 10 mg/ml, twice daily for 3 weeks following OHT‐induction. IOPs were recorded in both eyes at baseline (BL), day1, week1, 2, and 3 using a Tonopen. Animals were in vivo imaged for retinal ganglion cell (RGC) apoptosis in both eyes using DARC (Detection of Apoptotic Retinal Cells) at BL and week3 before culled. Retinal whole‐mounts were immunostained with a Brn‐3a antibody to assess RGC survival. DARC spots and RGC counts were assessed by blinded algorithm analysis.ResultsSurgical procedure induced a significant increase in IOP profiles in all animal groups compared to the contralateral eye (OD), and peak levels occurred at day1 (p < 0.001). In the OHT eyes treated with VSN16S, IOPs at week1 exhibited a sharp reduction (p < 0.05), and integrate IOP at week3 was significantly lower than vehicle controls (p < 0.01). However, AG020 showed no effect on IOP. IOP elevation resulted in a significant increase in DARC counts (RGC apoptosis) in all groups, compared to the baseline. DARC counts revealed a significant reduction in the OHT eyes treated by VSN16S, compared to the OHT‐only and vehicle groups (p < 0.01), but less of a reduction of DARC counts was observed with AG‐020 treatment (p < 0.05). A significant reduction of Brn‐3a+RGC density was seen in the OHT‐only group compared to naïve controls (p < 0.05), and VSN16S treatment demolished the difference although no significance was found on Brn‐3a+RGC density between VSN16S and controls.ConclusionsVSN16S exerted neuroprotective properties in OHT‐induced RGC loss, which may be associated with lowering IOP profiles. DARC is a useful tool in the assessment of drug efficacy in retinal neurodegenerative diseases.