Comparative effects of early postnatal ibuprofen and indomethacin on VEGF, IGF-I, and GH during rat ocular development.
OBJECTIVE
Ibuprofen and indomethacin are nonselective prostaglandin synthetase inhibitors that have been shown to improve oxygen-induced retinopathy in mice. Vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-I, and growth hormone (GH) are potent growth factors involved in retinal development. This study was conducted to examine and compare the effects of early postnatal ibuprofen and indomethacin on ocular and systemic VEGF, IGF-I, and GH during rat ocular development.


METHODS
Newborn rats were treated with intraperitoneal injections of low and high doses of ibuprofen or indomethacin at birth (postnatal day [P]1) and on P2 and P3. A control group received equivalent volumes of saline. At P14, vitreous fluid, retinal homogenates, and serum were analyzed for VEGF, IGF-I, and GH protein levels. Retinal mRNA expression of VEGF splice variants (VEGF188, VEGF164, VEGF120), VEGF receptors (VEGFR-1, VEGFR-2, Npn-1, Npn-2), and pigment epithelium-derived factor (PEDF) were also examined.


RESULTS
Animals treated with high-dose ibuprofen had significantly lower somatic growth and higher serum and vitreous IGF-I levels. High-dose ibuprofen decreased retinal VEGF levels and retinal VEGF164, VEGF120, and VEGFR-2 transcripts, resulting in a significant increase in the cecal period in 87% of rats at P14. Both indomethacin doses suppressed retinal VEGF164 transcripts without affecting VEGF receptors.


CONCLUSIONS
Ibuprofen may be more effective than indomethacin for suppression of retinal VEGF signaling, suggesting a possible therapy for retinal neovascularization. However, deficits in somatic growth concurrent with higher systemic IGF-I levels suggests decreased IGF-I bioactivity. These adverse effects should be considered.
Beharry
Kay D A
KD
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California Irvine, Irvine, and Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Miller Children's Hospital, Long Beach, California, USA.
Modanlou
Houchang D
HD
Hasan
Jamal
J
Gharraee
Zahra
Z
Abad-Santos
Patricia
P
Sills
Jeremy H
JH
Jan
Amanda
A
Nageotte
Stephen
S
Aranda
Jacob V
JV
D000818:Animals; D000831:Animals, Newborn; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005123:Eye / Q000254:growth & development*; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D014822:Vitreous Body / Q000187:drug effects* / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D040262:Receptors, Vascular Endothelial Growth Factor; D007052:Ibuprofen; D007213:Indomethacin