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.
Hewett
Sandra J
SJ
Department of Neuroscience, Program in Cellular and Molecular Pharmacology, University of Connecticut School of Medicine, Farmington, Connecticut, USA. shewett@neuron.uchc.edu
Silakova
Janna M
JM
Hewett
James A
JA
D000818:Animals; D015153:Blotting, Western; D001929:Brain Edema / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D006624:Hippocampus / Q000473:pathology*; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008845:Microinjections; D016202:N-Methylaspartate / Q000633:toxicity; D009288:Naproxen / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000517:prevention & control*; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents; D013450:Sulfones / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018690:Excitatory Amino Acid Agonists; D007783:Lactones; D018696:Neuroprotective Agents; D013450:Sulfones; C116926:rofecoxib; D009288:Naproxen; D016202:N-Methylaspartate