8-epi-prostaglandin-f2alpha and Retinopathy-of-Prematurity

Caffeine or ketorolac decrease the risk of retinopathy of prematurity and may act synergistically to improve beneficial effect. Combination of caffeine (Caff) and ketorolac (Keto) to prevent oxygen-induced retinopathy was studied.. Newborn rats exposed to room air (RA) or intermittent hypoxia (IH) consisting of 12% O2 during hyperoxia (50% O2) from birth (P0) had single daily IP injections of Caff from P0-P13 or saline; and/or ocular Keto (Acuvail, 0.45% ophthalmic solution) administered subcutaneously over the eyes from P5-P7. Pups were studied at P14 or placed in RA for recovery from IH (IHR) until P21. Eyes were examined for neovascularization, histopathology, growth factors, and VEGF-signaling genes.. Severe retinal damage noted during IHR in the untreated groups evidenced by hemorrhage, neovascularization, and oxygen-induced retinopathy (OIR) pathologies were prevented with Keto/Caff treatment. Keto and/or Caff treatment in IH also promoted retinal neural development evidenced by eye opening (92%, P < 0.001 vs. 31% in the placebo-treated IH group). No corneal pathologies were noted with Keto.. Caff or Keto given individually reduced retinal neovascularization, but the two drugs given together prevented severe OIR.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Apyrase; Arteries; Body Weight; Caffeine; Central Nervous System Stimulants; Choroid; Citrates; Dinoprost; Drug Synergism; Female; Hemorrhage; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Ketorolac; Neovascularization, Pathologic; Oxygen; Rats; Rats, Sprague-Dawley; Retina; Retinopathy of Prematurity; Signal Transduction; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Extremely low gestational age neonates (ELGANs) requiring oxygen therapy often experience frequent episodes of intermittent hypoxia (IH) and are at high risk for severe retinopathy of prematurity (ROP). Using an established model for oxygen-induced retinopathy (OIR), we examined the hypothesis that there is a critical number of daily brief IH episodes which will result in irreversible retinal oxidative damage.. Newborn rats were exposed to increasing daily clustered IH episodes (12% O₂ with 50% O₂) from postnatal day (P) 0 to P7 or P0 to P14, or placed in room air (RA) until P21 following 7- or 14-day IH. RA littermates at P7, P14, and P21 served as controls. A group exposed to constant 50% O₂ (CH) served as a second control. Blood gases, eye opening at P14, retinal, and choroidal oxidative stress and lipid peroxidation (8-isoPGF(2α)), oxidants (H₂O₂) and antioxidants (catalase and SOD), retinal pathology (adenosine diphosphatase (ADPase)-stained retinal flatmounts), and mitochondria-related genes were assessed.. pO₂ levels were higher with increasing IH episodes and remained elevated during the reoxygenation period. High SO₂ levels were associated with most severe OIR. Levels of all measured biomarkers peaked with six IH episodes and decreased with 8 to 12 episodes. H₂O₂ accumulated in the choroid during the reoxygenation period with irreversible retinal damage.. Our data suggest that six is the maximum number of IH episodes that the retina can sustain. Accumulation of H₂O₂ in the choroid may result in high levels being delivered to the entire retina, ultimately resulting in irreversible retinal oxidative damage.

Topics: Animals; Animals, Newborn; Blood Gas Analysis; Catalase; Choroid; Dinoprost; Disease Models, Animal; Female; Hydrogen Peroxide; Hypoxia; Lipid Peroxidation; Male; Oxidative Stress; Oxygen; Oxygen Inhalation Therapy; Pregnancy; Rats; Rats, Sprague-Dawley; Retinopathy of Prematurity; Risk Factors; Superoxide Dismutase

To investigate the role of oxidative stress in the pathogenesis of retinal injury induced by hyperoxia.. Sixty immature Sprague-Dawley (SD) rats born at a gestational age of 21 days, were randomly exposed to room air (air group, n=30) or 95% oxygen (hyperoxia group, n=30) immediately after birth. Plasma 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) levels were determined by ELISA. The ultrastructures of the retina were observed under a transmission electron microscope.. The plasma 8-iso-PGF2alpha contents of the air group were 19.09 +/-5.57, 18.24+/-5.91 and 17.00 +/- 5.58 pg/mL on the 3rd, 7th and 14th days after birth, respectively (F=1.024, P> 0.05). The plasma 8-iso-PGF2 contents in the hyperoxia group on the 3rd (28.33 +/- 5.59 pg/mL), the 7th day (51.20 +/- 15.01 pg/mL) and 14th day (84.54 +/- 14.85 pg/mL) after birth were significantly higher than those of the air group (t=2.863, P< 0.05; t=5.073, P< 0.01; t=11.006, P< 0.01). Moreover, the plasma 8-iso-PGF2 contents in the hyperoxia group increased with the prolonged hyperoxia exposure (F=150.7, P < 0.01). The ultrastructures of retina in the air group were normal. Hyperoxia exposure resulted in abnormalities of the ultrastructures of retina, manifesting as the membrane discs rarefied, twisted and disrupted and mitochondrial swelling.. Oxidative stress can results in retinal injury in immature rats. An increased plasma level of 8-iso-PGF2alpha is related to the injury degree of retina.

Topics: Animals; Dinoprost; Humans; Hyperoxia; Infant, Newborn; Lipid Peroxidation; Oxidative Stress; Rats; Rats, Sprague-Dawley; Retina; Retinopathy of Prematurity