Mefenamate, an agent that fails to attenuate experimental cerebral infarction.
BACKGROUND
Blockade of nonselective cation channels is a potential therapeutic approach that has not been attempted in cerebral ischemia, in spite of the ability of these channels to allow cellular calcium influx into neurons. Fenamates are a class of molecules that block these channels, and many congeners are also anti-inflammatory and free radical scavenging. These three mechanisms may contribute to brain damage in ischemia.


METHODS
Pretreatment or posttreatment with mefenamate (30 mg/kg) was evaluated in a temperature-controlled rat transient focal ischemia model. Quantitative histopathology on 26 coronal sections allowed determination of tissue necrosis and tissue atrophy at one week survival.


RESULTS
Neither pre- nor postischemic administration of a dose previously shown effective in preventing epileptic neuronal necrosis was found to reduce necrosis in cortex, nor in any subcortical structures.


CONCLUSIONS
We conclude that nonselective cation channel blockade with mefenamate affords no neuroprotection in this model. Publication bias against negative studies exists in the literature, but we here report negative findings due to the multiple potentially positive actions of the drug. Closer examination of the effects of the molecule, however, reveals several potentially negative effects as well. We conclude there may be inherent weakness in pharmacologic monotherapy, even with molecules having protean potentially beneficial effects. This conclusion seems to have been borne out by the results of recent clinical trials.
Kelly
John J
JJ
Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
Auer
Roland N
RN
D000818:Animals; D001284:Atrophy; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002412:Cations / Q000378:metabolism; D002544:Cerebral Infarction / Q000473:pathology*; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology*; D009336:Necrosis; D051381:Rats; D017208:Rats, Wistar
D002412:Cations; D007473:Ion Channels; D008528:Mefenamic Acid