Cyclooxygenase-2 inhibition provides lasting protection... : Critical Care Medicine (original) (raw)

Laboratory Investigations

Cyclooxygenase-2 inhibition provides lasting protection against neonatal hypoxic-ischemic brain injury*

Fathali, Nancy BS; Ostrowski, Robert P. MD, PhD; Lekic, Tim BS; Jadhav, Vikram MD, PhD; Tong, Wenni MS; Tang, Jiping MD; Zhang, John H. MD, PhD

From the Departments of Human Pathology and Anatomy (NF), Physiology (RPO, TL, VJ, WT, JT, JHZ), Neurosurgery (JHZ), and Anesthesiology (JHZ), Loma Linda University, Loma Linda, CA.

This study was funded, in part, by Grants HD43120 and NS54685 from the National Institutes of Health (JHZ).

The authors have not disclosed any potential conflict of interest.

For information regarding this article, E-mail: [email protected]

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.