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Oral treatment with rofecoxib reduces hippocampal excitotoxic neurodegeneration.

Hewett SJ, Silakova JM, Hewett JA

Department of Neuroscience, Program in Cellular and Molecular Pharmacology, University of Connecticut School of Medicine, Farmington, Connecticut, USA. shewett@neuron.uchc.edu

The purpose of this study was to determine whether the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib [4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone] could effectively prevent hippocampal neuronal injury in an animal model of excitotoxic neurodegeneration. COX-2 protein levels increased between 3 and 6 h, peaked at 12 h, and declined to near baseline levels 24 h after injection of N-methyl-d-aspartate (NMDA; 18 nmol) into the CA1 region of the left hippocampus. Mice that were fed ad libitum a control rodent diet for 4 days before and 3 days after injection of NMDA demonstrated marked neuronal loss in the primary cell layers of the ipsilateral CA1, CA3, and dentate gyrus (50, 30, and 20% cell loss, respectively). This injury was potently and dose-dependently reduced by feeding animals a diet standardized to deliver 15 or 30 mg/kg rofecoxib per day. Neurodegeneration in the CA1 region was reduced by 30.1 +/- 5.6 and 51.5 +/- 9.0%, respectively; in the CA3 by 64.6 +/- 12.4 and 69.0 +/- 14.1%, respectively; and in the dentate gyrus by 47.8 +/- 15.2 and 58.0 +/- 18.2%, respectively. Moreover, rofecoxib chow slightly but significantly reduced injury-induced brain edema. These findings demonstrate that rofecoxib can ameliorate excitotoxic neuronal injury in vivo and, as such, may be a particularly promising pharmaceutical for the treatment of neurological diseases associated with overactivation of NMDA receptors.

Published 19 November 2006 in J Pharmacol Exp Ther, 319(3): 1219-24.
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