Pharmacologic synergism of ocular ketorolac and systemic caffeine citrate in rat oxygen-induced retinopathy

Aranda, Jacob V.; Cai, Charles L.; Ahmad, Taimur; Bronshtein, Vadim; Sadeh, Jonathan; Valencia, Gloria; Lazzaro, Douglas R.; Beharry, Kay D.

doi:10.1038/pr.2016.105

Cited by 35 publications

(49 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data from the homogenates were standardized using total cellular protein levels as previously described [29, 31–34]. Validation studies comparing serum and plasma VEGF levels show no differences [35].…”

Section: Methodsmentioning

confidence: 99%

Ocular Adverse Effects of Intravitreal Bevacizumab Are Potentiated by Intermittent Hypoxia in a Rat Model of Oxygen-Induced Retinopathy

Tan

Cai

Shrier

et al. 2017

Journal of Ophthalmology

Self Cite

View full text Add to dashboard Cite

Intravitreal bevacizumab (Avastin) use in preterm infants with retinopathy of prematurity is associated with severe neurological disabilities, suggesting vascular leakage. We examined the hypothesis that intermittent hypoxia (IH) potentiates intravitreal Avastin leakage. Neonatal rats at birth were exposed to IH from birth (P0)–P14. At P14, the time of eye opening in rats, a single dose of Avastin (0.125 mg) was injected intravitreally into the left eye. Animals were placed in room air (RA) until P23 or P45 for recovery (IHR). Hyperoxia-exposed and RA littermates served as oxygen controls, and equivalent volume saline served as the placebo controls. At P23 and P45 ocular angiogenesis, retinal pathology and ocular and systemic biomarkers of angiogenesis were examined. Retinal flatmounts showed poor peripheral vascularization in Avastin-treated and fellow eyes at P23, with numerous punctate hemorrhages and dilated, tortuous vessels with anastomoses at P45 in the rats exposed to IH. These adverse effects were associated with robust increases in systemic VEGF and in both treated and untreated fellow eyes. Histological analysis showed severe damage in the inner plexiform and inner nuclear layers. Exposure of IH/IHR-induced injured retinal microvasculature to anti-VEGF substances can result in vascular leakage and adverse effects in the developing neonate.

show abstract

Section: Methodsmentioning

confidence: 99%

Ocular Adverse Effects of Intravitreal Bevacizumab Are Potentiated by Intermittent Hypoxia in a Rat Model of Oxygen-Induced Retinopathy

Tan

Cai

Shrier

et al. 2017

Journal of Ophthalmology

Self Cite

View full text Add to dashboard Cite

show abstract

“…This clustering design has been shown to produce severe oxidative stress in neonatal rats [35–40]. There were two IH groups corresponding to 7-day (P0-P7), and 14-day (P0-P14).…”

Section: Methodsmentioning

confidence: 99%

Chronic Intermittent Hypoxia Causes Lipid Peroxidation and Altered Phase 1 Drug Metabolizing Enzymes in the Neonatal Rat Liver

Cai

Aranda

Valencia

et al. 2017

ROS

View full text Add to dashboard Cite

Critically ill preterm neonates requiring oxygen therapy often experience frequent apneas with intermittent hypoxia (IH). IH-induced oxidative stress causes lipid peroxidation, which targets the liver and contributes to toxic drug reactions. We tested the hypothesis that incremental IH episodes induce oxidative damage in the neonatal liver and alter the expression of genes that regulate drug metabolism. Newborn rats were exposed to increasing IH episodes (12% O2) during hyperoxia (50% O2), or placed in room air (RA) until postnatal day 21 (P21) for recovery from IH (IHR). RA littermates served as controls, and pups exposed to 50% O2 served as hyperoxia controls. Hepatic histopathology, biomarkers of oxidative stress and oxidative DNA damage, antioxidants, and expression of genes that regulate drug metabolism were assessed. Oxidative stress and DNA damage, evidenced by 8-isoprostaglandin F2α (8-isoPGF2α) and 8-hydroxy-2′-deoxyguanosine (8-OH-dG), respectively, increased as a function of IH episodes, and was associated with decreased superoxide dismutase (SOD) and increased catalase activities. Pathological changes including cellular swelling, steatosis, necrosis, and focal sinusoid congestion were seen in IH, but not in IHR. Similarly, IH was associated with upregulation of several genes involved in DNA repair, which were downregulated during IHR. Of the genes involved in drug metabolism, aldehyde dehydrogenases (involved in lipid peroxidation) and cytochrome P450 (CYP) genes of the 2C family (involved in oxidative stress) were robustly upregulated both in IH and in IHR. Hepatic oxidative stress and lipid peroxidation occurring in response to chronic IH have implications for preterm infants, and may explain, in part, the pharmacokinetic variations and drug toxicities in this vulnerable population.

show abstract

“…Considering the safety profile of caffeine (20) and the ability of caffeine to control angiogenic factors, hypoxia‐inducible factor‐1α and VEGF (21, 22), angiogenesis (22, 23) and apoptosis of endothelium cells (24), and other vascular actions (25), this clinical observation raises an exciting possibility that caffeine may protect against pathologic neovascularization in ROP; however, this therapeutic strategy against ROP has not been directly tested. A recent study demonstrated that ocular ketorolac and systemic caffeine individually or synergistically reduced retinal neovascularization in rat oxygen‐induced retinopathy (OIR) (26). Several critical issues, such as the selectivity of caffeine effects on normal retinal vascularization development from pathologic angiogenesis, effective therapeutic window, and the actual molecular pharmacologic targets have not been addressed experimentally.…”

mentioning

confidence: 99%

Caffeine preferentially protects against oxygen‐induced retinopathy

Zhang

Zhou

et al. 2017

FASEB j.

View full text Add to dashboard Cite

Retinopathy of prematurity (ROP) is the leading cause of childhood blindness, but current anti-VEGF therapy is concerned with delayed retinal vasculature, eye, and brain development of preterm infants. The clinical observation of reduced ROP severity in premature infants after caffeine treatment for apnea suggests that caffeine may protect against ROP. Here, we demonstrate that caffeine did not interfere with normal retinal vascularization development but selectively protected against oxygen-induced retinopathy (OIR) in mice. Moreover, caffeine attenuated not only hypoxia-induced pathologic angiogenesis, but also hyperoxia-induced vaso-obliteration, which suggests a novel protection window by caffeine. At the hyperoxic phase, caffeine reduced oxygen-induced neural apoptosis by adenosine A receptor (AR)-dependent mechanism, as revealed by combined caffeine and AR-knockout treatment. At the hypoxic phase, caffeine reduced microglial activation and enhanced tip cell formation by AR-dependent and -independent mechanisms, as combined caffeine and AR knockout produced additive and nearly full protection against OIR. Together with clinical use of caffeine in neonates, our demonstration of the selective protection against OIR, effective therapeutic window, adenosine receptor mechanisms, and neuroglial involvement provide the direct evidence of the novel effects of caffeine therapy in the prevention and treatment of ROP.-Zhang, S., Zhou, R., Li, B., Li, H., Wang, Y., Gu, X., Tang, L., Wang, C., Zhong, D., Ge, Y., Huo, Y., Lin, J., Liu, X.-L., Chen, J.-F. Caffeine preferentially protects against oxygen-induced retinopathy.

show abstract

Pharmacologic synergism of ocular ketorolac and systemic caffeine citrate in rat oxygen-induced retinopathy

Cited by 35 publications

References 40 publications

Ocular Adverse Effects of Intravitreal Bevacizumab Are Potentiated by Intermittent Hypoxia in a Rat Model of Oxygen-Induced Retinopathy

Ocular Adverse Effects of Intravitreal Bevacizumab Are Potentiated by Intermittent Hypoxia in a Rat Model of Oxygen-Induced Retinopathy

Chronic Intermittent Hypoxia Causes Lipid Peroxidation and Altered Phase 1 Drug Metabolizing Enzymes in the Neonatal Rat Liver

Caffeine preferentially protects against oxygen‐induced retinopathy

Contact Info

Product

Resources

About