title: Cyclooxygenase-2 inhibition provides lasting protection against neonatal hypoxic-ischemic brain injury.
abstract: OBJECTIVE
  To investigate whether inhibition of cyclooxygenase-2, a critical component of the inflammatory pathway, is neuroprotective in a neonatal rat model of cerebral hypoxia-ischemia. The development of brain inflammation largely contributes to neonatal brain injury that may lead to a lifetime of neurologic deficits.
  
  
  METHODS
  Laboratory investigation.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Postnatal day ten Sprague-Dawley rats.
  
  
  METHODS
  Neonatal hypoxia-ischemia was induced by ligation of the right common carotid artery followed by 2 hrs of hypoxia (8% oxygen). The pups in treatment groups were administered 10 mg/kg (low dose) or 30 mg/kg (high dose) of a known selective cyclooxygenase-2 inhibitor (NS398). Animals were euthanized at three time points: 72 hrs, 2 wks, or 6 wks. Inflammation outcomes were assessed at 72 hrs; brain damage was assessed at 2 wks and 6 wks along with other organs (heart, spleen). Detailed neurobehavioral examination was performed at 6 wks.
  
  
  RESULTS
  Pharmacologic inhibition of cyclooxygenase-2 markedly increased survivability within the first 72 hrs compared with untreated rats (100% vs. 72%). Low- and high-dose NS398 significantly attenuated the loss of brain and body weights observed after hypoxia-ischemia. Neurobehavioral outcomes were significantly improved in some parameters with low-dose treatment, whereas high-dose treatment consistently improved all neurologic deficits. Immunohistochemical results showed a marked decrease in macrophage, microglial, and neutrophil abundance in ipsilateral hemisphere of the NS398-treated group along with a reduction in interleukin-6 expression.
  
  
  CONCLUSIONS
  Selective cyclooxygenase-2 inhibition protected neonatal rats against death, progression of brain injury, growth retardation, and neurobehavioral deficits after a hypoxic-ischemic insult.
authors.affiliation: Department of Human Pathology and Anatomy, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Fathali
authors.forename: Robert P
authors.initials: RP
authors.lastname: Ostrowski
authors.forename: Tim
authors.initials: T
authors.lastname: Lekic
authors.forename: Vikram
authors.initials: V
authors.lastname: Jadhav
authors.forename: Wenni
authors.initials: W
authors.lastname: Tong
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D020925:Hypoxia-Ischemia, Brain / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control; D015850:Interleukin-6 / Q000096:biosynthesis; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009578:Nitrobenzenes / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D015850:Interleukin-6; D018696:Neuroprotective Agents; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2