Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2004 The Effects of Aniracetam Treatment on Cognitive Performance and AMPA Receptor GluR2 Subunit Expression After Moderate Fluid Percussion Injury in Rats Anna Igorevna Baranova Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Psychology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/799 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. i THE EFFECTS OF ANIRACETAM TREATMENT ON COGNITIVE PERFORMANCE AND AMPA RECEPTOR GLUR2 SUBUNIT EXPRESSION AFTER MODERATE FLUID PERCUSSION INJURY IN RATS A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University By Anna I. Baranova Virginia Commonwealth University Director: Robert J. Hamm Professor Department of Psychology Virginia Commonwealth University Richmond, VA September, 2004 ii Acknowledgements To Denis Kashin 3/14/1975 – 7/21/1995 iii Table of Contents LIST OF FIGURES ........................................................................................................... vi LIST OF ABBREVIATIONS........................................................................................... vii ABSTRACT....................................................................................................................... ix INTRODUCTION ...............................................................................................................1 Overview of TBI......................................................................................................1 EPIDEMIOLOGY OF TBI..................................................................................................2 Incidence..................................................................................................................2 The cost of TBI ........................................................................................................4 Types of injury.........................................................................................................5 Severity of injury .....................................................................................................6 Mild TBI ......................................................................................................7 Moderate TBI...............................................................................................7 Severe TBI ...................................................................................................8 Cognitive and behavioral deficits ............................................................................8 THERAPEUTIC INTERVENTIONS ...............................................................................10 Pharmacological Strategies....................................................................................11 Inhibiting apoptosis................................................................................................11 a-Adenoreceptor agonists.......................................................................................11 Cholinergic agents .................................................................................................12 Kinin antagonists ...................................................................................................13 Cyclo-oxygenase-2 inhibitors ................................................................................14 Intracellular adhesion molecule antagonists ..........................................................15 NMDA receptor antagonists ..................................................................................16 AMPA Receptor antagonist ...................................................................................23 Magnesium sulfate.................................................................................................23 Dexanabinol ...........................................................................................................26 Estratrienes.............................................................................................................27 Calcium antagonists...............................................................................................28 LOE-908 ................................................................................................................29 MS-153 ..................................................................................................................29 iv Cyclosporin............................................................................................................30 Antioxidants...........................................................................................................31 Nitric oxide inhibitors............................................................................................33 Corticotrophin releasing factor ..............................................................................33 Growth factors .......................................................................................................34 Stem cells...............................................................................................................35 EXPERIMENTAL BRAIN INJURY ................................................................................36 Injury Pathology.....................................................................................................37 Fluid percussion injury model ...............................................................................42 AMPA RECEPTORS ........................................................................................................44 AMPA receptor properties.....................................................................................44 GluR2 subunit ........................................................................................................46 AMPA and TBI......................................................................................................47 ANIRACETAM.................................................................................................................48 Aniracetam properties............................................................................................48 Aniracetam in animal studies.................................................................................50 Aniracetam in clinical studies................................................................................52 LEARNING AND MEMORY ..........................................................................................54 Hippocampus .........................................................................................................55 Hippocampus structures.........................................................................................55 Entorhinal cortex........................................................................................55 Dentate gyrus .............................................................................................56 Hippocampus proper..................................................................................57 Subiculum ..................................................................................................58 Hippocampus and neurotransmitter systems .........................................................58 Hippocampus and TBI ...........................................................................................59 SUMMARY.......................................................................................................................60 METHODS ........................................................................................................................64 Subjects..................................................................................................................64 Fluid percussion apparatus.....................................................................................64 Injury model...........................................................................................................65 Surgical Preparation and Injury .............................................................................65 Outcome assessment ..............................................................................................66 v Morris water maze .....................................................................................67 GluR2 immunohistochemistry...............................................................................68 Rationale for selection ...............................................................................68 Procedure ...................................................................................................68 Drug treatment: Aniracetam ..................................................................................69 Experiment 1: Optimum dose determination.........................................................70 Design ........................................................................................................70 Analysis......................................................................................................70 Experiment 2: Delayed chronic