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Date of Award
Dissertation - Pacific Access Restricted
Doctor of Philosophy (Ph.D.)
Physiology and Pharmacology
Robert F. Halliwell
First Committee Member
John C. Livesey
Second Committee Member
Third Committee Member
Fourth Committee Member
James A. Uchizono
Fifth Committee Member
Stroke is a devastating neurological disease with limited treatment opportunities. Recent advances in understanding the underlying pathogenesis of cerebral ischemia support the involvement of multiple biochemical pathways in the development of the ischemic injury.
The work reported in this thesis was undertaken to investigate the hypothesis that fenamate NSAIDs have neuroprotective properties against ischemic stroke and to explore the underlying mechanisms for any efficacy.
Fenamates are non-selective inhibitors of cyclooxygenases. In addition, fenamates are antagonists of non-selective cation channels, subtype-selective modutators of GABAA receptors, weak inhibitors of glutaniate receptors and activators of some potassium channels, all potentially important in the pathogenesis of ischemic stroke, Mefenamic acid, a prototype fenamate, administered by intracerebroventricular (ICV) infusion, reduced the ischemic brain damage and edema volume in the middle cerebral artery occlusion model in male rats. Consistent with these results; systemic administration of mefenamic acid, by multiple intravenous injections, also reduced the ischemic damage and edema volume measured by morphometric analysis and as a function of brain water content. These are the first set of experiments to demonstrate a significant neuroprotective effect of a fenamate against an in vivo model of ischemic stroke.
In vitro, mefenamic acid was also shown to reduce glutamate-evoked cell death (excitotoxicity) in a concentration-dependent manner in cultured embryonic rat hippocampal neurons. Similarly, selected other fenamates also reduced excitotoxicity in the rank order (from highest): mefenamic acid > flufenamic acid ≥ meclofenamic acid > niflumic acid supporting the idea that this is a drug class action.
Three pharmacological properties of fenamates, cyclooxygenase inhibition, GABAA receptor modulation and potassium channel activation were investigated as the potential mechanism(s} for the neuroprotective effects of mefenamic acid against excitotoxicity. The experimental results suggest that these are not the primary mechanisms for neuroprotective effects of mefenamic acid against glutamate-evoked cell death.
Collectively, these data support the hypothesis that fenamate NSAIDs are neuroprotective against experimental models of cerebral ischemia and suggest they should be further investigated as potential pharmacological treatments for stroke.
Khanasari, Parto S.. (2007). An investigation of the neuroprotective properties of fenamate NSAIDs, against experimental model of ischemic stroke. University of the Pacific, Dissertation - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/671
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