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Sternum. ^Sympathetic Chain \ to Prevertebral Durham E-Theses An electrophysiological study of the interaction between fenamate NSAIDs and the GABA(_A) receptor Patten, Debra How to cite: Patten, Debra (1999) An electrophysiological study of the interaction between fenamate NSAIDs and the GABA(_A) receptor, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/4561/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk 2 An electrophysiological study of the interaction between Fenamate NSAIDs and the GABAA receptor. Debra Patten Submitted for the Degree of Ph.D. The copyright of this thesis rests with the author. No quotation from it should be published without the written consent of the author and information derived from it should be acknowledged. 1 9 JUL 2000 Dept. of Biological Sciences University of Durham March 1999 March 1999 Table of Contents AN ELECTROPHYSIOLOGICAL STUDY OF THE INTERACTION BETWEEN FENAMATE NSAIDs AND THE GABAA RECEPTOR CHAPTER ONE: GENERAL INTRODUCTION 1.1. An overview of the hypothesis addressed in this thesis 1 1.2. Non-Steroidal Anti-inflammatory Drugs fNSAIDs) 3 1.2.L Mechanism of action of NSAIDs. 3 1.2.H. Classification of NSAIDs 5 1.2.HL Analgesic Effects of NSAIDs 8 1.2. Hi. i. Peripheral antinociceptive effects. 8 1.2. Hi. n. Central antinociceptive effects 8 1.2. Hi. m. Alternative Mechanisms for analgesic effects of NSAIDs in the CA/S 9 1.2.iv. NSAIDs and neuroplasticity 10 1.2.V. Novel Clinical Applications of NSAIDs. 11 1.2.v. i. Ischaemia and Neuroprotection 11 1.2.v. a. Alzheimer's Disease 12 1.2.vi. The effect of prostaglandins on seizure models 13 1.2.vii. NSAIDs used in seizure models 14 1.2.viii. Physiological effects of NSAIDs on ion channel function 17 1.2.viii. i. Non-neuronalpreparations 17 1.2.viii. ii. Neuronal Preparations . 18 1.3. Ligand-Gated Ion Channels-genera/ features 20 1.4. The Y-Aminobutvric Acid Type A (GABAA) Receptor 20 1.4.1. y-Aminobutyric Acid (GABA) 20 1.4.H. GABA Receptor Classification 21 1.4.iii. Structure of the GABAA receptor 22 1.4.iv. Biophysical Properties of the GABAA receptor 25 1.4.v. Subunit Heterogeneity & Stoichiometry of GABA Receptors 26 1.5. GABAa Receptor Pharmacology: 30 1.5.L Agonists 30 1.5.U. Partial Agonists 31 1.5.HL Competitive Antagonists 33 1.5.iv. Non-competitive antagonists 36 ii 1.6. Positive Allosteric Modulators of the GABAA Receptor 37 1.6.L Benzodiazepine Modulation of the GAB A A Receptor 38 1.6.H. Steroidal Modulation of the GABAA Receptor 40 1.6.HL Barbiturate Modulation of the GABAA Receptor 42 1.6.iv. Modulation of the GAB A A Receptor & Other Neuronal Ligand-gated Ion Channels by propofol. 44 1.6.v. Loreclezole & its Action at the GABAA Receptor 48 1.6.vi. Negative Allosteric Modulators of the GABAA Receptor 50 1.6.vii. NSAIDs, Quinolones & the GABAA Receptor 50 1.7. Fenamate modulation of GABA^ -gated chloride channels 51 1.8. Aims of This Study 53 CHAPTER TWO: GENERAL METHODS 2.1. EXTRACELLULAR RECORDING METHODS 55 2.1.i.Vagus Nerve Dissection 55 2.1.ii. Optic Nerve Dissection 55 2.2. Electrophysiological recording from rat vagus and optic nerve 58 2.2./. Drugs and Solutions 59 2.2.ii. Experimental Protocol 60 2.2.Hi. Data analysis 61 2.3. WHOLE-CELL VOLTAGE-CLAMP RECORDING METHODS 61 2.3./. Hippocampal dissection 62 2.3. H. Methods for cell culture maintenance 65 2.4. Whole-Cell Voltage Clamp Recording 69 2.4. /. Drugs and Solutions 72 2AM. Experimental Protocol .73 2.4.HL Data Analysis 73 CHAPTER THREE:RESULTS Section 3.1 : Modulation of agonist-evoked responses of the rat vagus and optic nerves by mefenamic acid . 1. Introduction 75 2. Procedures 75 3. Pharmacological characterization of agonist-evoked responses in vagus and optic nerves 76 4. Results 76 4.i Pharmacological characterization of agonist-evoked responses in the rat isolated vagus nerve. 76 4.N. Pharmacological characterisation of agonist-evoked responses in the rat isolated optic nerve. 77 4.iii. Allosteric modulation of the GABA-mediated response in the rat isolated vagus nerve. 78 4.iv. Selectivity of action of propofol on vagus and optic nerves. 79 4. v. Mefenamic acid potentiates the GABA-mediated response in the rat isolated vagus nerve. 80 5. Discussion _ 80 5.i. Characterisation of agonist-evoked responses in vagus and optic nerves. 80 5.N. Allosteric modulation of the GABA-mediated response in the rat isolated vagus nerve. 83 5.iii. Selectivity of action of propofol on vagus and optic nerves 84 5.iv. Mefenamic acid potentiates the GABA-mediated response in the rat isolated vagus nerve. 88 Section 3.2: Electrophysiological and neuropharmacological properties of cultured rat hippocampal neurones. 1.Introduction 89 2. Electrophysiological Characteristics of Hippocampal Neurones 89 3. Procedures 90 4. Results- Ligand-gated Anion Channels 91 4./. Physiological and pharmacological properties of GABA-evoked currents (lGABA) 91 (a) l-V Relationship of(lGABA) 91 (b) Pharmacology of (IGABA)_ 91 4.N.Physiological and pharmacological properties of glycine-evoked currents (I g)yclne) _ 92 (a)Pharmacology of the (I giycine) 93 iv 5. Results- Ligand-gated Cation Channels _ 93 5.i. ionotropic Glutamate Receptors 93 5.i. Physiological and pharmacological properties of NMDA-evoked currents CINMDA) 93 (a) l-V Relationship of{\mQf} 93 (b) Pharmacology of{\mo/d -.93 5.ii. Physiological and pharmacological properties of AMPA-evoked currents (lAMPA) 94 (a) l-V Relationship gl{\mPA) 94 (b) Pharmacology of_(\mpi) ...94 5.iii. Physiological and pharmacological properties of kainic acid-evoked currents (lkainicacid) 94 (a) l-V Relationship of (lkainicacid) 94 (b) Pharmacology of(lkainicacid) 95 6. Discussion 95 Section 3.3: Determination on the effect, site and molecular mechanism of action of fenamates at neuronal GABA^ receptors 1. Introduction 98 2. Procedures ...98 3. Results .....99 3. i. Mefenamic acid potentiates GABA-evoked whole-cell currents 99 3.ii. Determination of the effects of non-fenamate NSAIDs on GABA- evoked whole-cell currents 100 3.iii. Modulation of GABA-evoked whole cell currents by fenamate NSAIDs 100 3.iv. The potentiating effects of mefenamic acid are not mediated via the benzodiazepine site of the GABAA receptor. 101 3.v. The potentiating effects of mefenamic acid are not due to GABA uptake inhibition .102 3.vi. The potentiating effects of mefenamic acid are not due to membrane perturbation. 103 3.vii. The modulatory effects of niflumic acid and mefenamic acid are not use-dependent 104 3.vii. i. Procedures 104 3.vii. ii. Results 105 v 3.viii. The potentiating effects of mefenamic acid are voltage-dependent 105 3.viii. i. Procedures 105 3.viii. ii. Results 106 3.ix. Mefenamic acid directly activates the GABAA receptor 106 3.ix. i. Procedures 106 3.ix. n. Results- Mefenamic acid alone activates an inward current 107 3.ix. iii. Current-voltage relationship of mefenamic acid-activated currents 107 3.x. Sensitivity to the modulatory effects of mefenamic acid varies across hippocampal neurones 108 3. xi.. Mefenamic acid acts at or shares a recognition site with loreclezole 108 4. Summary- modulation of GABA-evoked responses in hippocampal neurones by mefenamic acid. 109 RESULTS: Chapter 4 Determination of the effects of mefenamic acid on other neuronal ligand-gated ion channels 1. Introduction 111 2. Methods 111 3. Results 112 3.i. Glycine 112 3. H. NMDA 112 3.iii. AMPA 113 3.iv. Kainate 113 4. Summary 114 CHAPTER FIVE: General Discussion 1 .The selectivity of action of propofol 1.1.5 2. Mefenamic acid potentiates GABA-evoked responses in voltage-clamped rat hippocampal neurones .1.19 vi 3. Inhibition of GABA-evoked responses by fenamates in hippocampal neurones 121 4. Fenamate Structure-activity relationships at native GABAA receptors 122 5. Possible site(s) and molecular mechanism(s) of action of mefenamic acid at native GABAA receptors 124 5.i. The role of the "benzodiazepine site" for the modulation of GABA currents by mefenamic acid or 124 5.H. Possible mechanisms of action of mefenamic acid on neuronal GABAA receptors 125 5.Hi. Potentiation of GABA currents by fenamates and GABA re-uptake inhibitiors. .1.25 5.iv. Mefenamic acid-induced modulation of GABA currents and inhibition of prostaglandin synthesis ? .125 5. v. Modulation of GABA currents by membrane perturbation ...126 5. vi. Modulation of GABA currents by changes in receptor protein phosphorylation 1.27 5. vii. Use- and Voltage-dependence of the effects of mefenamic acid and niflumic acid on GABAA receptors. 128 5. viii. Neuronal sensitivity to mefenamic acid varies across cultured hippocampal neurones- similarities to loreclezole? 1132 5./x. Overlapping sites and/or transduction mechanisms for mefenamic acid and loreclezole? 134 5. x. Evidence for direct activation of the GABAA receptor by mefenamic acid. 135 6.
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