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. 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.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Fathali N,Ostrowski RP,Lekic T,Jadhav V,Tong W,Tang J,Zhang JH

doi

10.1097/CCM.0b013e3181cb1158

subject

Has Abstract

pub_date

2010-02-01 00:00:00

pages

572-8

issue

2

eissn

0090-3493

issn

1530-0293

journal_volume

38

pub_type

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