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Mefenamate, an Agent that Fails to Attenuate Experimental Cerebral Infarction

Published online by Cambridge University Press:  02 December 2014

John J. Kelly  and
Roland N. Auer
John J. Kelly
Affiliation:
Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, AB Canada
Roland N. Auer
Affiliation:
Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, AB Canada
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Abstract

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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.

Résumé:

RÉSUMÉ:Contexte:

Le blocage des canaux cationiques non sélectifs est une approche thérapeutique potentielle qui n’a pas été tentée dans l’ischémie cérébrale malgré la capacité qu’ont ces canaux de permettre l’influx de calcium cellulaire dans les neurones. Les fénamates sont une classe de molécules qui bloquent ces canaux et plusieurs d’entre eux sont également anti-inflammatoires et anti-radicalaires. Ces trois mécanismes peuvent contribuer au dommage cérébral dans l’ischémie.

Méthodes:

Le prétraitement ou le post-traitement par le méfénamate (30mg/kg) a été évalué dans un modèle murin d’ischémie focale transitoire sous temperature contrôlée. L’histopathologie quantitative de 26 sections coronales a permis d’identifier la nécrose tissulaire et l’atrophie après une semaine de survie.

Résultats:

Ni l’administration pré ou post ischémie n’a diminué la nécrose du cortex ou de structures sous-corticales.

Conclusions:

Nous concluons que le blocage de canaux cathioniques non sélectifs au moyen du méfénamate ne confère aucune neuroprotection chez ce modèle. Il existe dans la littérature un biais de publication contre les études dont les résultats sont négatifs. Nous rapportons ici des résultats négatifs à cause des multiples effets positifs potentiels de ce médicament. Cependant, un examen plus poussé des effets de cette molécule révèle également plusieurs effets négatifs potentiels. Nous concluons qu’il existe peut-être des faiblesses inhérentes à la monothérapie pharmacologique, même avec des molécules qui ont des effets bénéfiques potentiels protéiformes. Les résultats d’essais cliniques récents semblent appuyer cette conclusion.

Type
Experimental Neurosciences
Information
Canadian Journal of Neurological Sciences , Volume 30 , Issue 3 , August 2003 , pp. 259 - 262
Copyright
Copyright © The Canadian Journal of Neurological 2003

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