Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

NCX 470, a Dual Acting Nitric Oxide (NO)-Donating Bimatoprost Derivative, Preserves Rabbit Eyes from Biochemical and Functional Changes Associated with ET-1-Induced Ischemia/Reperfusion Injury

Silvia Sgambellone
* ORCID logo ,
Silvia Marri
ORCID logo ,
Serafina Villano
,
Emanuela Masini
,
Gustavo Provensi
ORCID logo ,
Elena Bastia
,
Corinna Galli
,
Stefania Brambilla
ORCID logo ,
Francesco Impagnatiello
,
Laura Lucarini
ORCID logo
Version 1 : Received: 28 April 2023 / Approved: 5 May 2023 / Online: 5 May 2023 (06:00:47 CEST)

How to cite: Sgambellone, S.; Marri, S.; Villano, S.; Masini, E.; Provensi, G.; Bastia, E.; Galli, C.; Brambilla, S.; Impagnatiello, F.; Lucarini, L. NCX 470, a Dual Acting Nitric Oxide (NO)-Donating Bimatoprost Derivative, Preserves Rabbit Eyes from Biochemical and Functional Changes Associated with ET-1-Induced Ischemia/Reperfusion Injury. Preprints 2023, 2023050309. https://doi.org/10.20944/preprints202305.0309.v1 Sgambellone, S.; Marri, S.; Villano, S.; Masini, E.; Provensi, G.; Bastia, E.; Galli, C.; Brambilla, S.; Impagnatiello, F.; Lucarini, L. NCX 470, a Dual Acting Nitric Oxide (NO)-Donating Bimatoprost Derivative, Preserves Rabbit Eyes from Biochemical and Functional Changes Associated with ET-1-Induced Ischemia/Reperfusion Injury. Preprints 2023, 2023050309. https://doi.org/10.20944/preprints202305.0309.v1

Abstract

NCX 470, a nitric oxide (NO)-donating bimatoprost, was shown to ameliorate ocular hemodynamics and retinal physiology in rabbits following endothelin-1 (ET-1)-induced ischemia/reperfusion. Here we used the same model to compare NCX 470 (0.1% bid) to Lumigan® (bimatoprost 0.01% ophthalmic solution, LUM) and bimatoprost administered at equimolar dose as NCX 470 (0.072%, BIM). Intraocular pressure (IOP), ophthalmic artery resistive index (OA-RI) and electroretinogram (ERG) were computed prior to treatment and at various time-points thereafter. Gluthatione (GSH), 8-Hydroxy-2-deoxyguanosine (8-OH2dG), Interleukin-1beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6) and Caspase-3 protein expression and activity were determined in retina at week 6. ET-1 increased IOP (VEHIOP_Baseline=20.5±0.8 and VEHIOP_Week6=24.8±0.3mmHg) and OA-RI (VEHOA-RI_Baseline=0.36±0.02 and VEHOA-RI_Week6=0.55±0.01) while it reduced rod/cone responses. Oxidative stress, inflammation and apoptotic markers were also increased in ET-1-treated eyes. NCX 470 prevented IOP (NCX 470IOP_Week6=18.1±0.6mmHg) and OA-RI (NCX 470OA-RI_Week6=0.33±0.01) changes and restored ERG amplitude; these effects were only partially shared by LUM or BIM. Additionally, NCX 470 reduced oxidative stress, inflammation and apoptosis in retina of treated eyes. BIM and LUM were numerically less effective on these parameters. Data suggest that NCX 470 repeated ocular dosing ameliorates ocular hemodynamics and retinal cell dysfunction consequent to ischemia/reperfusion via both, NO- and bimatoprost-mediated mechanisms.

Keywords

nitric oxide; bimatoprost; ischemia/reperfusion; oxidative stress; inflammation; apoptosis

Subject

Medicine and Pharmacology, Medicine and Pharmacology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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