title: Dexamethasone pre-treatment protects brain against hypoxic-ischemic injury partially through up-regulation of vascular endothelial growth factor A in neonatal rats.
abstract: Dexamethasone (Dex) provides neuroprotection against subsequent hypoxia ischemia (HI) in newborn rats, but the mechanism of this neuroprotection is not well understood. It is known that vascular endothelial growth factor A (VEGF) has neuroprotective effects. The objective of this study was to evaluate the role of the VEGF signaling pathway in the Dex-induced neuroprotection in newborn rats. Seven-day-old rat pups had the right carotid artery permanently ligated followed by 140 or 160 min of hypoxia (8% oxygen). Rat pups received two i.p. injections of either saline or Dex (0.25 mg/kg) at 24 and 4 h before HI exposure. To quantify the effects of a glucocorticoid receptor (GR) blocker, on postnatal day (PD) 6 and 15 min prior to Dex treatment rat pups received s.c. vehicle or RU486 (GR blocker, 60 mg/kg). After 24 h at PD 7, all rat pups had HI as described earlier. To quantify the effects of a VEGFR 2 blocker, at 24 h after Dex/Veh treatment (PD7), SU5416, a VEGFR 2 inhibitor or vehicle was injected intracerebroventricularly in the right hemisphere at 30 min before and 2 h after HI. Dex pre-treatment reduced brain injury and enhanced the HI-induced brain VEGF protein while a GR blocker inhibited these effects. Treatment with VEGFR 2 blocker decreased Dex-induced neuroprotection also. Dex pre-treatment enhanced the HI-induced increase in mRNA expression of VEGF splice variants and decreased the HI-induced reduction of Akt phosphorylation. Additionally, it also decreased HI-induced increase of caspase-3 activity and DNA fragments in neonatal rat brain. We conclude that Dex provides robust neuroprotection against subsequent HI in newborn rats via GR likely with the partial involvement of VEGF signaling pathway.
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.forename: P G
authors.initials: PG
authors.lastname: Rhodes
authors.forename: A J
authors.initials: AJ
authors.lastname: Bhatt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D003907:Dexamethasone