The Endothelin Receptor Antagonist Macitentan Attenuates Neurodegeneration in a Rodent Model of Glaucoma

Abstract

Purpose : Glaucoma is a neurodegenerative disease, commonly associated with elevated intraocular pressure (IOP) and characterized by cupping of the optic disk, optic nerve degeneration, apoptosis of retinal ganglion cells (RGCs), which could lead to loss of vision. Our previous studies suggested that the ET_B receptor plays a causative role in promoting neurodegeneration of optic nerve axons and loss of RGCs in rats with elevated IOP. Recent work from our laboratory demonstrated that the ET_A receptor is also upregulated in the retinas of IOP elevated rats. This brings up possibilities of developing endothelin receptor antagonists as neuroprotective agents in glaucoma. The purpose of this study was to determine if the dual ET_A/ET_B receptor antagonist, macitentan, could attenuate neurodegenerative changes following IOP elevation in Brown Norway rats.

Methods : IOP was elevated for either 2 or 4 weeks in one eye of adult male Brown Norway rats, while the corresponding contralateral eye served as control. Brown Norway rats that were IOP elevated for 4 weeks were either untreated or treated (in dietary gels) for 1 month with macitentan (5 or 10 mg/kg/body weight) during IOP elevation. Retinal flat mounts obtained from the rats were stained with antibodies to either RBPMS or Brn3a and surviving RGCs were imaged and quantitated. Rats were assessed for RGC function by pattern ERG analysis following 2 and 4 weeks of IOP elevation and macitentan treatment.

Results : IOP elevation for 4 weeks produced a 42-61% loss of RGCs. Rats fed with macitentan during IOP elevation displayed significantly lower (6-31%) RGC loss, compared to IOP elevated untreated rats. However, macitentan treatment did not alter the IOP in these rats. Pattern ERG analysis revealed a 22-25% decrease in amplitude following IOP elevation. Macitentan treatment was found to significantly protect against the IOP-mediated decline in pattern ERG amplitude. Following 2 and 4 weeks of IOP elevation and macitentan treatment, there was 100% and 87% preservation of PERG amplitude respectively, indicative of maintenance of RGC function.

Conclusions : Blocking both ET_A and ET_B receptors by oral administration of the endothelin receptor antagonist, macitentan, could have neuroprotective effects by enhancing RGC survival and function without affecting IOP.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.