Oral treatment with rofecoxib reduces hippocampal excitotoxic neurodegeneration

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.