Abstract
Given the complexity of oxygen-induced retinopathy (OIR), we tested the hypothesis that combination therapies and modes of administration would synergistically optimize efficacy for prevention of OIR. Newborn rats were exposed to neonatal intermittent hypoxia (IH) from the first day of life (P0) until P14 during which they received: (1) oral glutathione nanoparticles (nGSH) with topical ocular phosphate buffered saline (PBS); (2) nGSH with topical ocular Acuvail (ACV); (3) oral coenzyme Q10 (CoQ10) + ACV; (4) oral omega 3 polyunsaturated fatty acids (n-3 PUFAs) + ACV; (5) CoQ10 + n-3 PUFAs + PBS; or (6) CoQ10 + n-3 PUFAs + ACV. Treated groups raised in room air (RA) served as controls. At P14, pups were placed in RA with no treatment until P21. Retinal vascular pathology, ocular angiogenesis biomarkers, histopathology, and morphometry were determined. All combination treatments in IH resulted in the most beneficial retinal outcomes consistent with suppression of angiogenesis growth factors during reoxygenation/reperfusion and no significant adverse effects on somatic growth. nGSH + PBS also reversed IH-induced retinopathy, but had negative effects on growth. Simultaneously targeting oxidants, inflammation, and poor growth mitigates the damaging effects of neonatal IH on the developing retina. Therapeutic synergy with combination delivery methods enhance individual attributes and simultaneously target multiple pathways involved in complex diseases such as OIR.
Highlights
Retinopathy of prematurity (ROP) is a potentially blinding disease that afflicts predominantly extremely low gestational age neonates (ELGANs) who are ≤28 weeks gestation [1,2,3,4]
Percentage change in body weight and body length from birth were determined at P7, P14, and P21 in order to establish the effects of oral supplementation and/or topical ocular ACV on anthropometric growth
In the room air (RA) groups, oral nGSH and topical ocular phosphate buffered saline (PBS) consistently resulted in the highest weight accretion at all time intervals
Summary
Retinopathy of prematurity (ROP) is a potentially blinding disease that afflicts predominantly extremely low gestational age neonates (ELGANs) who are ≤28 weeks gestation [1,2,3,4]. 3 polyunsaturated fatty acids (n-3 PUFAs), targeting oxidants and/or growth deficits, were individually effective for ameliorating specific characteristics consistent with ROP [8]. These individual supplements did not completely prevent severe oxygen-induced retinopathy (OIR) and many unwanted retinal pathologies persisted. Based on their individual therapeutic benefits, the current study was conducted to determine whether combined treatments and mode of delivery, simultaneously targeting the key underlying pathways, i.e., oxidative distress, inflammation, and poor growth would optimize their individual mechanistic attributes, reduce barrier limitations, and therapeutically synergize to prevent severe IH-induced OIR
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