Abstract
Purpose :
The endothelin system has been shown to be a contributor to neurodegeneration in rodent models of glaucoma. The purpose of this study was to determine if the endothelin receptor antagonist, macitentan, could promote neuroprotection by blocking endothelin-1 (ET-1) mediated vasoconstrictive changes as well as reduce RGC loss and axonal injury during ocular hypertension.
Methods :
Adult retired breeder male and female Brown Norway rats were either untreated or treated with macitentan (5 mg/kg body wt) in dietary gels three days per week. Following the treatments, the rats were intravitreally injected in one eye with 4 ml of 500 mM ET-1 and the retinal vasculature was imaged in a Micron IV retinal imaging system. In a parallel set of experiments IOP was elevated in one eye of Brown Norway rats and the animals were treated with macitentan for 4 weeks in dietary gels. Pattern ERG analysis, RGC counts and PPD staining of optic nerve sections were carried out.
Results :
ET-1 administration produced rapid vasoconstrictive effects in retinal arteries that occurred 5 min after intravitreal administration and recovery began to occur 20 minutes post-injection. Rats treated with macitentan in the diet abrogated the ET-1 mediated vasoconstrictive effects or delayed its onset. Following IOP elevation in rats, untreated rats exhibited a significant 32% loss of RGCs, compared to naïve rats. Dietary administration of macitentan (5 mg/kg) significantly (p<0.01) enhanced the survival of RGCs (5% RGC loss), significantly (p<0.01) protected against optic nerve axonal injury and a trend towards preservation of PERG amplitude (not significant).
Conclusions :
Blocking both ETA and ETB receptors by oral administration of the endothelin receptor antagonist, macitentan, may protect from hypoxic injury as well as promote RGC survival during ocular hypertension. Endothelin receptor antagonists could potentially act through both vascular and cellular mechanisms to promote neuroprotection in glaucoma.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.