RESUMEN
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.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/farmacología , Hipocampo/patología , Lactonas/farmacología , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/prevención & control , Fármacos Neuroprotectores , Sulfonas/farmacología , Animales , Western Blotting , Edema Encefálico/patología , Muerte Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/farmacología , Agonistas de Aminoácidos Excitadores/toxicidad , Masculino , Ratones , Microinyecciones , N-Metilaspartato/toxicidad , Naproxeno/farmacología , Neuronas/patologíaRESUMEN
The purpose of this study was to examine the optimal dose and therapeutic window of opportunity of the nonsteroidal anti-inflammatory drug naproxen in an animal model of excitotoxic neuronal injury. Injection of N-methyl-D-aspartate (NMDA; 18-20 nmol) into the CA1 region of the left hippocampus resulted in significant brain edema as measured by the percentage of total forebrain water content that occurred 24 h after intrahippocampal microinjection of NMDA with approximately 50% loss of CA1 neurons assessed 72 h later. Naproxen pretreatment (20 mg/kg) resulted in significantly less brain edema. Ten, 15, or 20 mg/kg naproxen, administered systemically 1 day (b.i.d.) before and for 3 days after (b.i.d.) NMDA injection, attenuated the neuronal damage by 27.2 +/- 7.8, 39.6 +/- 11.1, and 57.0 +/- 5.2%, respectively. By comparison, a single dose of MK-801 (2 mg/kg i.p.) given 20 min before NMDA injection inhibited subsequent hippocampal injury by 65.6 +/- 8.8%. Most importantly, neuroprotection was still evident when naproxen treatment (20 mg/kg i.p.) was initiated 6 h after NMDA microinjection. Protection was lost if administration of naproxen was delayed for 20 h. These findings demonstrate that naproxen can prevent excitotoxic neuronal injury in vivo, that it is nearly as effective as direct NMDA receptor antagonism, and that it has an extended therapeutic time window. As such, naproxen may be a particularly promising pharmaceutical for the treatment of neurological diseases associated with overactivation of NMDA receptors.