Evidence for neuroprotection by the fenamate NSAID, mefenamic acid

Document Type

Article

Publication Title

Neurochemistry International

ISSN

0197-0186

Volume

55

Issue

7

DOI

10.1016/j.neuint.2009.06.014

First Page

683

Last Page

688

Publication Date

12-1-2009

Abstract

Fenamate NSAIDs are inhibitors of cyclooxygenases, antagonists of non-selective cation channels, subtype-selective modulators of GABA receptors, weak inhibitors of glutamate receptors and activators of some potassium channels. These pharmacological actions are all implicated in the pathogenesis of ischemic stroke. The aim of this study was to investigate the hypothesis that the fenamate, mefenamic acid, is neuroprotective in an in vitro and in vivo model of stroke. Embryonic rat hippocampal neurons were cultured and maintained for up to 14 days in vitro. At 9 or 14 days, cells were exposed to glutamate (5 μM) or glutamate (5 μM) plus mefenamic acid (10-100 μM) or the control agent, MK-801 (10 μM) for 10 min. 24 h later, cell death was determined by measuring lactate dehydrogenase (LDH) levels in the culture media. In vivo, male Wistar rats (300-350 g) were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. Animals received either a single i.v. dose of MFA (10 mg/kg or 30 mg/kg), or MK-801 (2 mg/kg) or saline prior to MCAO or, four equal doses of MFA (20 mg/kg) at 1 h intervals beginning 1 h prior to MCAO. Ischemic damage was then assessed 24 h after MCAO. In vitro, mefenamic acid (10-100 μM) and MK-801 (10 μM) significantly reduced glutamate-evoked cell death compared with control cultures. In vivo, MFA (20 mg/kg × 4) significantly reduced infarct volume, total ischemic brain damage and edema by 53% (p ≤ 0.02), 41% (p ≤ 0.002) and 45% (p ≤ 0.002) respectively. Furthermore, mefenamic acid reduced cerebral edema when measured as a function of brain water content. MK-801 was also neuroprotective against MCAO brain injury. This study demonstrates a significant neuroprotective effect by a fenamate NSAID against glutamate-induced cell toxicity, in vitro and against ischemic stroke in vivo. Further experiments are currently addressing the mechanism(s) of this neuroprotection. © 2009 Elsevier Ltd. All rights reserved. A

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