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Characterization of the interaction between fenamates and hippocampal neuron GABA A receptors
Fenamate NSAIDs have several central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels...
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Published in: | Neurochemistry international 2007-11, Vol.51 (6), p.440-446 |
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creator | Coyne, Leanne Su, Jiping Patten, Debra Halliwell, Robert F. |
description | Fenamate NSAIDs have several
central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels expressed in cultured rat hippocampal neurons. All fenamates tested (1–100
μM) dose-dependently potentiated GABA-evoked currents; mefenamic acid (MFA) was the most potent and efficacious and was found to shift the GABA dose–response curve to the left without effect on the maximum amplitude or the GABA Hill Slope. The modulation of GABA receptors by MFA was not reduced in the presence of the benzodiazepine antagonist, flumazenil (10
μM) and was moderately voltage-dependent. MFA at concentrations ≥10
μM evoked dose-dependent currents in the absence of GABA. These currents were potentiated by diazepam (1
μM) and blocked by bicuculline (10
μM). The MFA (50
μM) current–voltage relationship and reversal potential were similar to that evoked by GABA. MFA (1–100
μM) had no effects on sub-maximal glycine, glutamate or NMDA evoked currents. These data show that fenamate NSAIDs are a highly effective class of GABA
A receptor modulator and activators. |
doi_str_mv | 10.1016/j.neuint.2007.04.017 |
format | article |
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central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels expressed in cultured rat hippocampal neurons. All fenamates tested (1–100
μM) dose-dependently potentiated GABA-evoked currents; mefenamic acid (MFA) was the most potent and efficacious and was found to shift the GABA dose–response curve to the left without effect on the maximum amplitude or the GABA Hill Slope. The modulation of GABA receptors by MFA was not reduced in the presence of the benzodiazepine antagonist, flumazenil (10
μM) and was moderately voltage-dependent. MFA at concentrations ≥10
μM evoked dose-dependent currents in the absence of GABA. These currents were potentiated by diazepam (1
μM) and blocked by bicuculline (10
μM). The MFA (50
μM) current–voltage relationship and reversal potential were similar to that evoked by GABA. MFA (1–100
μM) had no effects on sub-maximal glycine, glutamate or NMDA evoked currents. These data show that fenamate NSAIDs are a highly effective class of GABA
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central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels expressed in cultured rat hippocampal neurons. All fenamates tested (1–100
μM) dose-dependently potentiated GABA-evoked currents; mefenamic acid (MFA) was the most potent and efficacious and was found to shift the GABA dose–response curve to the left without effect on the maximum amplitude or the GABA Hill Slope. The modulation of GABA receptors by MFA was not reduced in the presence of the benzodiazepine antagonist, flumazenil (10
μM) and was moderately voltage-dependent. MFA at concentrations ≥10
μM evoked dose-dependent currents in the absence of GABA. These currents were potentiated by diazepam (1
μM) and blocked by bicuculline (10
μM). The MFA (50
μM) current–voltage relationship and reversal potential were similar to that evoked by GABA. MFA (1–100
μM) had no effects on sub-maximal glycine, glutamate or NMDA evoked currents. These data show that fenamate NSAIDs are a highly effective class of GABA
A receptor modulator and activators.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Anticonvulsant</subject><subject>Cells, Cultured</subject><subject>Diazepam - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Electrophysiology</subject><subject>Fenamates - pharmacology</subject><subject>Flumazenil - pharmacology</subject><subject>GABA Antagonists - pharmacology</subject><subject>GABA Modulators - pharmacology</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Glutamate receptors</subject><subject>Glycine receptors</subject><subject>Hippocampus - drug effects</subject><subject>Hippocampus - metabolism</subject><subject>Membrane Potentials - drug effects</subject><subject>Membrane Potentials - physiology</subject><subject>Neural Inhibition - drug effects</subject><subject>Neural Inhibition - physiology</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>NSAID</subject><subject>Patch-Clamp Techniques</subject><subject>Rats</subject><subject>Receptors, GABA-A - drug effects</subject><subject>Receptors, GABA-A - metabolism</subject><subject>Synaptic Transmission - drug effects</subject><subject>Synaptic Transmission - physiology</subject><issn>0197-0186</issn><issn>1872-9754</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><recordid>eNo1kU1LAzEQhoMotn78A5GcvO06yWazuxehFq2C4EWPEtJklqZ0P0xSRX-9Ka2ngZmHl5l5CLlikDNg8nad97h1fcw5QJWDyIFVR2TK6opnTVWKYzIF1lQZsFpOyFkIa0hgA-UpmbCqlCBrOSUf85X22kT07ldHN_R0aGlcIU3JuBvsWkuM34g9bbHXnY4YqO4tXblxHIzuRr2haRWfwMXsfkZn1KPBMQ4-XJCTVm8CXh7qOXl_fHibP2Uvr4vn-ewlQ9aImC11abjmLQdjRGNaqNEWtSnYEqyuGBS8YcI0Ag2TtjZWFkaXJbdoq5JzVhbn5GafO_rhc4shqs4Fg5uN7nHYBiXrQoIQkMDrA7hddmjV6F2n_Y_6f0gC7vYApnW_HHoVjMPeoHXpqqjs4BQDtTOg1mpvQO0MKBAqGSj-AMjteto</recordid><startdate>20071101</startdate><enddate>20071101</enddate><creator>Coyne, Leanne</creator><creator>Su, Jiping</creator><creator>Patten, Debra</creator><creator>Halliwell, Robert F.</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20071101</creationdate><title>Characterization of the interaction between fenamates and hippocampal neuron GABA A receptors</title><author>Coyne, Leanne ; Su, Jiping ; Patten, Debra ; Halliwell, Robert F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-e194t-ba5c2a2f20cc49cf08ed38c31b0da71032914c94ec16d8cd63ca552ded7522153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Anticonvulsant</topic><topic>Cells, Cultured</topic><topic>Diazepam - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Electrophysiology</topic><topic>Fenamates - pharmacology</topic><topic>Flumazenil - pharmacology</topic><topic>GABA Antagonists - pharmacology</topic><topic>GABA Modulators - pharmacology</topic><topic>gamma-Aminobutyric Acid - metabolism</topic><topic>Glutamate receptors</topic><topic>Glycine receptors</topic><topic>Hippocampus - drug effects</topic><topic>Hippocampus - metabolism</topic><topic>Membrane Potentials - drug effects</topic><topic>Membrane Potentials - physiology</topic><topic>Neural Inhibition - drug effects</topic><topic>Neural Inhibition - physiology</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>NSAID</topic><topic>Patch-Clamp Techniques</topic><topic>Rats</topic><topic>Receptors, GABA-A - drug effects</topic><topic>Receptors, GABA-A - metabolism</topic><topic>Synaptic Transmission - drug effects</topic><topic>Synaptic Transmission - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Coyne, Leanne</creatorcontrib><creatorcontrib>Su, Jiping</creatorcontrib><creatorcontrib>Patten, Debra</creatorcontrib><creatorcontrib>Halliwell, Robert F.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Neurochemistry international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Coyne, Leanne</au><au>Su, Jiping</au><au>Patten, Debra</au><au>Halliwell, Robert F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of the interaction between fenamates and hippocampal neuron GABA A receptors</atitle><jtitle>Neurochemistry international</jtitle><addtitle>Neurochem Int</addtitle><date>2007-11-01</date><risdate>2007</risdate><volume>51</volume><issue>6</issue><spage>440</spage><epage>446</epage><pages>440-446</pages><issn>0197-0186</issn><eissn>1872-9754</eissn><abstract>Fenamate NSAIDs have several
central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels expressed in cultured rat hippocampal neurons. All fenamates tested (1–100
μM) dose-dependently potentiated GABA-evoked currents; mefenamic acid (MFA) was the most potent and efficacious and was found to shift the GABA dose–response curve to the left without effect on the maximum amplitude or the GABA Hill Slope. The modulation of GABA receptors by MFA was not reduced in the presence of the benzodiazepine antagonist, flumazenil (10
μM) and was moderately voltage-dependent. MFA at concentrations ≥10
μM evoked dose-dependent currents in the absence of GABA. These currents were potentiated by diazepam (1
μM) and blocked by bicuculline (10
μM). The MFA (50
μM) current–voltage relationship and reversal potential were similar to that evoked by GABA. MFA (1–100
μM) had no effects on sub-maximal glycine, glutamate or NMDA evoked currents. These data show that fenamate NSAIDs are a highly effective class of GABA
A receptor modulator and activators.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>17560686</pmid><doi>10.1016/j.neuint.2007.04.017</doi><tpages>7</tpages></addata></record> |
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subjects | Animals Anti-Inflammatory Agents, Non-Steroidal - pharmacology Anticonvulsant Cells, Cultured Diazepam - pharmacology Dose-Response Relationship, Drug Electrophysiology Fenamates - pharmacology Flumazenil - pharmacology GABA Antagonists - pharmacology GABA Modulators - pharmacology gamma-Aminobutyric Acid - metabolism Glutamate receptors Glycine receptors Hippocampus - drug effects Hippocampus - metabolism Membrane Potentials - drug effects Membrane Potentials - physiology Neural Inhibition - drug effects Neural Inhibition - physiology Neurons - drug effects Neurons - metabolism NSAID Patch-Clamp Techniques Rats Receptors, GABA-A - drug effects Receptors, GABA-A - metabolism Synaptic Transmission - drug effects Synaptic Transmission - physiology |
title | Characterization of the interaction between fenamates and hippocampal neuron GABA A receptors |
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