Evidence for neuroprotection by the fenamate NSAID, mefenamic acid.
Fenamate NSAIDs are inhibitors of cyclooxygenases, antagonists of non-selective cation channels, subtype-selective modulators of GABA(A) 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 (5microM) or glutamate (5microM) plus mefenamic acid (10-100microM) or the control agent, MK-801 (10microM) for 10min. 24h later, cell death was determined by measuring lactate dehydrogenase (LDH) levels in the culture media. In vivo, male Wistar rats (300-350g) were subjected to 2h middle cerebral artery occlusion (MCAO) followed by 24h reperfusion. Animals received either a single i.v. dose of MFA (10mg/kg or 30mg/kg), or MK-801 (2mg/kg) or saline prior to MCAO or, four equal doses of MFA (20mg/kg) at 1h intervals beginning 1h prior to MCAO. Ischemic damage was then assessed 24h after MCAO. In vitro, mefenamic acid (10-100microM) and MK-801 (10microM) significantly reduced glutamate-evoked cell death compared with control cultures. In vivo, MFA (20mg/kgx4) significantly reduced infarct volume, total ischemic brain damage and edema by 53% (p< or =0.02), 41% (p< or =0.002) and 45% (p< or =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.
Khansari
Parto S
PS
University of the Pacific, Stockton, CA 95211, USA.
Halliwell
Robert F
RF
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents; D008528:Mefenamic Acid; D018698:Glutamic Acid