Mechanisms Underlying Neuroprotection by the NSAID Mefenamic Acid in an Experimental Model of Stroke

Stroke is a devastating neurological event 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 damage. Fenamates are classical non-steroidal anti-inflammatory drugs but they are also highly subunit-selective modulators of GABAA receptors, activators of IKS potassium channels and antagonists of non-selective cation channels and the NLRP3 inflammosome. In the present study we investigated the effect of mefenamic acid (MFA) in a rodent model of ischemic stroke and then addressed the underlying pharmacological mechanisms in vitro for its actions in vivo. The efficacy of MFA in reducing ischemic damage was evaluated in adult male Wistar rats subjected to a 2-h middle cerebral artery occlusion. Intracerebroventricular (ICV) infusion of MFA (0.5 or 1 mg/kg) for 24 h, significantly reduced the infarct volume and the total ischemic brain damage. In vitro, the fenamates, MFA, meclofenamic acid, niflumic acid, and flufenamic acid each reduced glutamate-evoked excitotoxicity in cultured embryonic rat hippocampal neurons supporting the idea that this is a drug class action. In contrast the non-fenamate NSAIDs, ibuprofen and indomethacin did not reduce excitotoxicity in vitro indicating that neuroprotection by MFA was not dependent upon anti-inflammatory actions. Co-application of MFA (100 μM) with either of the GABAA antagonists picrotoxin (100 μM) or bicuculline (10 μM) or the potassium channel blocker tetraethylammonium (30 mM) did not prevent neuroprotection with MFA, suggesting that the actions of MFA also do not depend on GABAA receptor modulation or potassium channel activation. These new findings indicate that fenamates may be valuable in the adjunctive treatment of ischemic stroke

Mechanisms Underlying Neuroprotection by the NSAID Mefenamic Acid in an Experimental Model of Stroke

Stroke is a devastating neurological event 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 damage. Fenamates are classical non-steroidal anti-inflammatory drugs but they are also highly subunit-selective modulators of GABAA receptors, activators of IKS potassium channels and antagonists of non-selective cation channels and the NLRP3 inflammosome. In the present study we investigated the effect of mefenamic acid (MFA) in a rodent model of ischemic stroke and then addressed the underlying pharmacological mechanisms in vitro for its actions in vivo. The efficacy of MFA in reducing ischemic damage was evaluated in adult male Wistar rats subjected to a 2-h middle cerebral artery occlusion. Intracerebroventricular (ICV) infusion of MFA (0.5 or 1 mg/kg) for 24 h, significantly reduced the infarct volume and the total ischemic brain damage. In vitro, the fenamates, MFA, meclofenamic acid, niflumic acid, and flufenamic acid each reduced glutamate-evoked excitotoxicity in cultured embryonic rat hippocampal neurons supporting the idea that this is a drug class action. In contrast the non-fenamate NSAIDs, ibuprofen and indomethacin did not reduce excitotoxicity in vitro indicating that neuroprotection by MFA was not dependent upon anti-inflammatory actions. Co-application of MFA (100 μM) with either of the GABAA antagonists picrotoxin (100 μM) or bicuculline (10 μM) or the potassium channel blocker tetraethylammonium (30 mM) did not prevent neuroprotection with MFA, suggesting that the actions of MFA also do not depend on GABAA receptor modulation or potassium channel activation. These new findings indicate that fenamates may be valuable in the adjunctive treatment of ischemic stroke

An investigation of the neuroprotective properties of fenamate NSAIDs, against experimental models of ischemic stroke

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 modulators of GABA A receptors, weak inhibitors of glutamate 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 \u3e flufenamic acid ≥ meclofenamic acid \u3e niflumic acid supporting the idea that this is a drug class action. Three pharmacological properties of fenamates, cyclooxygenase inhibition, GABA A 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

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 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.

Impact of Completion of a Pre-Pharmacy Biochemistry Course and Competency Levels in Pre-Pharmacy Courses on Pharmacy Student Performance

Poor performance in foundational science courses, which are usually taken during the first or second year of pharmacy school, can have several negative consequences including increases in student drop-out rates and increases in the number of dismissals and remediating students. The primary goal of the current study was to determine whether completion of a pre-pharmacy biochemistry course and/or performance on a biochemistry competency test (administered at the beginning of the pharmacy program) are associated with pharmacy student performance in foundational science courses and overall academic performance. A secondary goal was to determine whether performance in pre-pharmacy courses and/or student demographics are associated with pharmacy student performance. Prospective univariate analyses (n = 75) determined that completion of a pre-pharmacy biochemistry course is not associated with pharmacy student performance. However, performance on a biochemistry competency test was associated with performance in Biochemistry and Cell&Molecular Biology (p = 0.002). Furthermore, post-hoc analyses determined that pre-pharmacy cumulative chemistry GPA correlates with performance in both the Biochemistry and Cell&Molecular Biology and Medicinal Chemistry foundational science courses (p = 0.002 and p = 0.04, respectively) and can predict first year GPA (p = 0.002). The combined data indicate that further assessment of the impact of pre-pharmacy competency in biochemistry and chemistry on pharmacy student success is warranted

Revisiting Faculty Citizenship

This commentary describes the significance of faculty citizenship in the broader context of institutional culture and defines faculty citizenship for use across all aspects of faculty roles in the Academy. The definition includes two key components (engagement and collegiality) that can be used to measure citizenship behaviors. Continued discussion and study of faculty citizenship will further the Academy’s understanding and use of the concept

Revisiting Faculty Citizenship

Faculty citizenship and institutional culture are critically important to the health and success of any college/school of pharmacy. This commentary describes the current relevance and importance of faculty citizenship in the broader context of institutional culture and provides a definition of faculty citizenship for use across all aspects of faculty roles in the pharmacy academy. The definition includes two key components (engagement and collegiality) that can be used to measure citizenship behaviors. Continued discussion and study of faculty citizenship will further the academy’s understanding and use of the concep