Abstract
Purpose :
NCX 1728 is a nitric oxide (NO)-donating phosphodiesterase-5 inhibitor under investigation for the treatment of retinopathies where enhanced neovascularization, vascular permeability, and inflammation are key pathophysiological features for disease progression. This work evaluates the ocular hemodynamic effects and neuroprotective activity of repeated topical ocular dosing of NCX 1728 in comparison to its des-nitro derivative (NCX 1880) administered at equimolar doses in rabbits with endothelin-1 (ET-1)-induced ischemia/reperfusion injury of optic nerve head and retina.
Methods :
ET-1 was injected next to the optic nerve head twice/week for 6 weeks. Animals received NCX 1728 (1% twice daily, 6 days/week), NCX 1880 (0.9%, equimolar to 1% NCX 1728) or vehicle from week 3 until the end of ET-1 treatment. Functional endpoints were ophthalmic artery resistive index (OA-RI) and photoreceptor function (electroretinogram, ERG) determined using an Echo-Color-Doppler and a Retimax apparatus, respectively.
Results :
ET-1 increased OA-RI over time [0.35±0.04, 0.47±0.05* and 0.52±0.02* at baseline, week 2 and 6, respectively (*p<0.05 vs baseline, n=4)]. Treatment with NCX 1728 restored baseline OA-RI (0.39±0.06, p<0.05 vs vehicle, n=4) by week 6. Conversely, the administration of NCX 1880 (des-nitro derivative) at equimolar doses as NCX 1728 resulted not effective (0.48±0.14, n=4). Photoreceptor response (dark-adapted 3.0) decreased after treatment with ET-1 (103.1±16.8, 78.0±19.5 and 88.0±23.8µV at baseline, week 2 and 6, respectively). NCX 1728 reversed this effect (106.0±28.9µV, p<0.05 vs vehicle) while NCX 1880 was only partially effective (98.7±25.4µV) at week 6.
Conclusions :
NCX 1728 ameliorates ocular perfusion as well as photoreceptor function following ET-1-induced ischemia/reperfusion injury of the optic nerve head and retina. These effects seem mostly NO-dependent as NCX 1880 which lacks the NO-donating moiety only resulted in partial activity. Additional studies are needed to establish whether the effects observed with NCX 1728 on ocular perfusion and retinal function are interdependent.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.