Combination Antioxidant/NSAID Therapies and Oral/Topical Ocular Delivery Modes for Prevention of Oxygen-Induced Retinopathy in a Rat Model

Abstract

<jats:p>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.</jats:p>

Biomarkers of lung alveolarization and microvascular maturation in response to intermittent hypoxia and/or early antioxidant/fish oil supplementation in neonatal rats

“…Recovery between each IH episode occurred in 50% O 2 following each clustered IH event for 2.5 h for a total of eight clustering IH episodes per day for 14 days, as previously described. [24][25][26] This clustering IH pattern was first reported in newborn rats by Coleman et al 30 Studies in preterm infants confirm that early patterns of IH put infants at risk for future development of severe ROP. 31…”

“…At P0, RA, and IH exposed pups were randomized to receive 50 µL oral supplementation of: (1) extra virgin olive oil (OO); (2) coenzyme Q10 (CoQ10) in OO; (3) oral fish oil; (4) glutathione nanoparticle sublingual drops (nGSH, 200 mg/mL, optimized for instant absorption) diluted to 24 µg in 50 µL with extra virgin OO; or (5) combination CoQ10 + fish oil from the 1st day of life (P0) to P14. The doses of CoQ10 and fish oil, and methods of daily supplementation, were based on previous findings 25,26 . CoQ10 is lipid soluble.…”

“…The doses of CoQ10 and fish oil, and methods of daily supplementation, were based on previous findings. 25,26 CoQ10 is lipid soluble. The choice for extra virgin oil was based on previous reports.…”

Comparison of coenzyme Q10 or fish oil for prevention of intermittent hypoxia-induced oxidative injury in neonatal rat lungs

“…Within 2–4 h of birth, newborn rat pups delivering on the same day were pooled and randomly assigned to expanded litters of 18 pups/litter (nine males and nine females) for each experimental group (Additional file 1 : Figure S1), as previously described [ 18 – 21 ]. Equal numbers for each gender in each group normalized gender differences.…”

“…Treatments were administered using an orogastric syringe. The doses of CoQ10 and fish oil were based on our previous data [ 20 , 21 ].…”