Naproxen reduces excitotoxic neurodegeneration in vivo with an extended therapeutic window

The purpose of this study was to examine the optimal dose and therapeutic window of opportunity of the nonsteroidal antiinflammatory 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 ≈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.