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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 9, 2004; DOI: 10.1124/jpet.103.063867

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Received for publication December 8, 2003.
Revised February 5, 2004.
Accepted for publication February 6, 2004.

Naproxen Reduces Excitotoxic Neurodegeneration In Vivo with an Extended Therapeutic Window

Janna M Silakova 1, James A Hewett 1, Sandra J. Hewett 1*

1 University of Connecticut Health Center

* Address correspondence to: E-mail: shewett{at}neuron.uchc.edu

Abstract

The purpose of this study was to examine the optimal dose and therapeutic window of opportunity of the non-steroidal anti-inflammatory drug naproxen in an animal model of excitotoxic neuronal injury. Injection of N-methyl-D-aspartate (NMDA; 18-20nmol) 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 hr following intrahippocampal microinjection of NMDA with {approx} 50% loss of CA1 neurons assessed 72 hr later. Naproxen pretreatment (20mg/kg) resulted in significantly less brain edema. Ten, 15 or 20 mg/kg naproxen, administered systemically one day (b.i.d.) prior to and for three 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 (2mg/kg, i.p.) given 20 min prior to NMDA injection inhibited subsequent hippocampal injury by 65.6 ± 8.8%. Most importantly, neuroprotection was still evident when naproxen treatment (20mg/kg, i.p.) was initiated six hr after NMDA microinjection. Protection was lost if administration of naproxen was delayed for 20hr. 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 over-activation of NMDA receptors.


Key words: cyclooxygenase, excitotoxicity, mouse, neurodegeneration, neuroprotection, non-steroidal anti-inflammatory drug


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S. J. Hewett, J. M. Silakova, and J. A. Hewett
Oral Treatment with Rofecoxib Reduces Hippocampal Excitotoxic Neurodegeneration
J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1219 - 1224.
[Abstract] [Full Text] [PDF]


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