Neuroprotective effects of an endothelin receptor antagonist in a rat model of ocular hypertension.

Purpose: Endothelin 1 is elevated in both patients and in animal models of glaucoma and has been shown to contribute to neurodegeneration. Since endothelin 1 acts through two receptors, endothelin A receptor and endothelin B receptor, the purpose of this study is to determine if antagonism of both endothelin receptors by Macitentan can promote neuroprotection during intraocular pressure (IOP) elevation in rats. Methods: IOP was elevated in the left eye of adult male retired breeder Brown Norway rats using Morrison’s model of ocular hypertension (injection of hypertonic saline through episcleral veins) and maintained for 4 weeks. Contralateral eyes served as the corresponding contralateral controls. Rats were then separated into treated and untreated groups, with the treated group receiving Macitentan (10 mg/kg) 3 times per week in the diet (administered in gel packs). After one month of treatment, rats were sacrificed and retinal flat mounts were prepared for both IOP elevated and contralateral eyes of both the treated and untreated rats. The flat mounts were immunostained for the retinal ganglion cell-specific marker Brn3a, imaged in a confocal microscope and masked cell counts were performed. Results: IOP elevation in untreated rats showed a dramatic decline in retinal ganglion cell counts compared to the contralateral controls, whereas rats treated with Macitentan showed significant preservation of retinal ganglion cell numbers. Conclusion: Currently, therapies for the treatment of glaucoma are solely focused on the reduction of IOP. The study described herewith demonstrates the ability of a dual endothelin receptor antagonist, Macitentan, to promote retinal ganglion cell survival independent of IOP. Due to its IOP independent action, this therapy could be developed for neuroprotection either independent or concurrent with available glaucoma therapies.