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. Design: Laboratory investigation. Setting: University research laboratory. Subjects: Postnatal day ten Sprague-Dawley rats. Interventions: 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. Measurements and Main 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. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.
Original language | English |
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Pages (from-to) | 572-578 |
Number of pages | 7 |
Journal | Critical Care Medicine |
Volume | 38 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2010 |
ASJC Scopus Subject Areas
- Critical Care and Intensive Care Medicine
Keywords
- Cerebral ischemia
- Cyclooxygenase-2
- Inflammation
- Neonatal
- Neuroprotection
- Stroke
- Animals, Newborn
- Body Weight/drug effects
- Hypoxia-Ischemia, Brain/prevention & control
- Interleukin-6/biosynthesis
- Inflammation/prevention & control
- Rats
- Neuroprotective Agents/pharmacology
- Rats, Sprague-Dawley
- Blotting, Western
- Brain/drug effects
- Dose-Response Relationship, Drug
- Animals
- Cyclooxygenase 2/biosynthesis
- Sulfonamides/pharmacology
- Behavior, Animal/drug effects
- Cyclooxygenase 2 Inhibitors/pharmacology
- Nitrobenzenes/pharmacology