Abstract
Purpose :
The A3AR is known as a therapeutic target for glaucoma treatment because the A3AR antagonists prevent chloride release and reduce aqueous humor production in nonpigmented epithelial cells in the ciliary body. The intraocular pressure (IOP) was reduced after treatment of A3AR antagonist and in A3AR knockout mice. In here, we have developed HL3501, a novel selective adenosine A3 antagonist. This study examined the selectivity profile and the in vitro and in vivo effects of HL3501.
Methods :
The binding assays and functional assay of A3AR were performed for selectivity. For the rabbit model (n=4/group), IOP was elevated by laser photocoagulation of trabecular meshwork(TM), and then, the rabbits were topically treated with HL3501(0.02%, BID), latanoprost(0.005%, BID) or vehicle for 3 weeks. The IOP of all rabbits was measured on days 0, 1, 3, 5, 7, 10, 14, 17 and 21. For the mouse model (n=8/group), topical ocular application of HL3501(0.04%, BID), latanoprost (0.005%, QD) or vehicle was administered following IOP elevation by dexamethasone(DEX). The IOP measurement date of the mouse model was the same as the rabbit model. The Electroretinography(ERG) was recorded from both eyes of dark-adapted anesthetized mice on days 0 and 21. The mice eyes were enucleated at the end of the treatment for immunofluorescence staining to characterize the proteins involved in extracellular matrix(ECM) remodeling in the TM. All animal experiments were performed appropriately in compliance with the IACUC guidelines.
Results :
Our study showed that HL3501 was highly specific to the A3AR as well as inhibitory of A3AR function in the in vitro assay. In the rabbit glaucoma model, HL3501 and latanoprost significantly inhibited the IOP. In the DEX-treated mouse model, HL3501 and latanoprost significantly ameliorated IOP elevation and reduction of b-wave amplitude, as compared with the vehicle group. HL3501 and latanoprost also reduced the increase of fibronectin and α-smooth muscle actin(SMA) by DEX-treatment.
Conclusions :
Data demonstrated that HL3501, a novel A3AR antagonist, had a similar effect with latanoprost in ocular hypertension animal models. Therefore, HL3501 could be used as a novel approach to treat glaucoma disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.