edited by josé miguel vela, rafael maldonado, michel hamon in … · university pierre & marie...

Edited byJosé Miguel Vela, Rafael Maldonado, Michel Hamon

Methods and Principles in Medicinal Chemistry

In vivo Models for Drug Discovery

Volume 62Series Editors:R. Mannhold, H. Kubinyi, G. Folkers

Edited by

José M. Vela, Rafael Maldonado, and

Michel Hamon

In VivoModels for Drug Discovery

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board

H. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland

Previous Volumes of this Series:

Liras, Spiros / Bell, Andrew S. (Eds.)

Phosphodiesterases and TheirInhibitors2014

ISBN: 978-3-527-33219-9

Vol. 61

Hanessian, Stephen (Ed.)

Natural Products in MedicinalChemistry2014

ISBN: 978-3-527-33218-2

Vol. 60

Lackey, Karen / Roth, Bruce (Eds.)

Medicinal ChemistryApproaches to PersonalizedMedicine2013

ISBN: 978-3-527-33394-3

Vol. 59

Brown, Nathan (Ed.)

Scaffold Hopping in MedicinalChemistry2013

ISBN: 978-3-527-33364-6

Vol. 58

Hoffmann, Rémy / Gohier, Arnaud /Pospisil, Pavel (Eds.)

Data Mining in Drug Discovery2013

ISBN: 978-3-527-32984-7

Vol. 57

Dömling, Alexander (Ed.)

Protein-Protein Interactions inDrug Discovery2013

ISBN: 978-3-527-33107-9

Vol. 56

Kalgutkar, Amit S. / Dalvie, Deepak /Obach, R. Scott / Smith, Dennis A.

Reactive Drug Metabolites2012

ISBN: 978-3-527-33085-0

Vol. 55

Brown, Nathan (Ed.)

Bioisosteres in MedicinalChemistry2012

ISBN: 978-3-527-33015-7

Vol. 54

Gohlke, Holger (Ed.)

Protein-Ligand Interactions2012

ISBN: 978-3-527-32966-3

Vol. 53

Kappe, C. Oliver / Stadler, Alexander /Dallinger, Doris

Microwaves in Organic andMedicinal ChemistrySecond, Completely Revised and Enlarged

Edition

2012

ISBN: 978-3-527-33185-7

Vol. 52

Edited by José M. Vela, Rafael Maldonado, and Michel Hamon

In VivoModels for Drug Discovery

Series Edi tors

Prof. Dr. Raimun d Man nholdRosenw eg 740489 DüsseldorfGermanymannhold @uni-duesseld orf.de

Prof. Dr. Hugo KubinyiDonnersbergstrasse 967256 Weisenheim am SandGermanykubinyi@t-o nline.de

Prof. Dr. Gerd FolkersCollegium HelveticumSTW/ETH Zurich8092 ZurichSwitzerland

Volume Editors

Dr. José M. VelaLaboratorios Dr. Esteve S.A.Drug Discovery & DevelopmentC/ Baldiri Reixac 4-808028 BarcelonaSpain

Dr. Rafael MaldonadoUniversity Pompeu Fabra. PRBBNeuropharmacology Lab.c/Dr. Aiguader 8808003 BarcelonaSpain

Prof. Michel HamonUniversity Pierre & Marie CurieNeuropharmacology, INSERM U894Site Pitié-Salpetrière 9175634 Paris, cedex 13France

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Contents

List of Contributors XIXPreface XXIXA Personal Foreword XXXI

Part I Transversal Issues Concerning Animal Models in Drug Discovery 1

1 The 3Ns of Preclinical Animal Models in Biomedical Research 3José Miguel Vela, Rafael Maldonado, and Michel Hamon

1.1 First N: The Need for Use of Animal Models 31.2 Second N: The Need for Better Animal Models 51.2.1 Unbiased Design 81.2.2 Comprehensive Reporting 81.2.3 Selection of the Animal Model Based on Its Validity Attributes 91.2.4 Appropriate Time and Dosing 111.2.5 Use of Biomarkers 121.2.6 Use of Various Animal Models 131.2.7 Quantitative, Multiple, and Cross-Predictive Measurements 141.2.8 Pharmacokinetic–Pharmacodynamic Integration 151.2.9 Predefinition and Adherence to the Desired Product Profile 161.2.10 Comparison with Gold Standard References 181.2.11 Reverse Translation/Backtranslation (Bedside-to-Bench

Approach) 181.3 Third N: The Need for 3Rs Guiding Principles 19

References 22

2 Alternative Models in Drug Discovery and Development Part I:In Silico and In VitroModels 27Luz Romero and José Miguel Vela

2.1 Introduction 272.2 In SilicoModels 342.2.1 Quantitative Structure–Activity Relationship 342.2.2 Biokinetic Modeling 37

jV

2.2.3 Disease- and Patient-Specific In SilicoModels 422.3 In VitroModels 432.3.1 Primary Cells, Cell Lines, Immortalized Cell Lines, and Stem Cells 442.3.2 Advanced In VitroModels for the Prediction of Drug Toxicity 462.3.3 In Vitro Tumor Models 47

References 50

3 Alternative Models in Drug Discovery and Development Part II:In Vivo Nonmammalian and Exploratory/ExperimentalHuman Models 59Luz Romero and Jos�e Miguel Vela

3.1 Introduction 593.2 In Vivo Nonmammalian Models 593.2.1 Zebrafish 613.2.2 D. melanogaster 663.2.3 C. elegans 713.3 In Vivo Exploratory and Experimental Human Models 743.3.1 Phase 0 (Exploratory Human Models): Microdosing Studies 763.3.2 Phase IB/IIA (Proof-of-Concept) Studies: Experimental Human

Models 81References 84

4 Ethical Issues and Regulations and Guidelines ConcerningAnimal Research 91David Sabat�e

4.1 Introduction 914.2 Current Use of Animals in Biomedical and Pharmaceutical

Research 924.3 Ethical Concerns and Positions on Animal Research 934.4 General Principles for the Ethical Use of Animals in Research 954.4.1 The 3Rs Principles (Replacement, Reduction, and Refinement) 954.4.2 The Principle of Justification 964.4.3 The Principle of Responsibility 974.5 Regulatory Framework for Use of Animals in Research 984.5.1 European Union 984.5.2 The United States 1004.5.3 Canada 1004.5.4 Japan 1004.5.5 Australia 1014.5.6 India 1014.5.7 China 1014.5.8 Brazil 1024.5.9 Countries without a Specific Legal Framework 102

Acknowledgment 102References 102

VIj Contents

5 Regulatory Issues: Safety and Toxicology Assessment 107Antonio Guzm�an

5.1 Introduction 1075.1.1 Animal Testing 1075.1.2 Regulatory Context 1095.1.3 Clinical Context 1095.2 Animal Species in Toxicology Studies 1105.2.1 Rodents 1115.2.2 Nonrodents 1125.2.3 Nonconventional Animal Models 1145.3 Toxicology Studies 1145.3.1 General Principles 1145.3.2 General and Repeated Dose Toxicity Studies 1165.3.3 Safety Pharmacology 1185.3.4 Genotoxicity 1195.3.5 Development and Reproductive Toxicity Studies 1225.3.6 Carcinogenicity Studies 1245.4 Translation to Clinics: Limitations and Difficulties 126

References 127

6 Generation and Use of Transgenic Mice in Drug Discovery 131Guillaume Pavlovic, Véronique Brault, Tania Sorg, and Yann H�erault

6.1 Introduction 1316.2 Improved Mouse Genetic Engineering 1336.2.1 Recent Technical Developments 1336.2.2 The Advent of New Mouse Mutant Resource:

One Stop Shop 1336.3 Functional Evaluation and Uses of Mouse Models 1366.3.1 Standardization and Harmonization 1366.3.2 Genetic Background and Environmental Influences 1376.3.3 Challenges Ahead 1376.3.4 Target Identification and Translation to Humans 1386.3.5 Use of GEMMs in Pharmaceutical Industry and Risk Assessment 1396.4 Translation to Clinics: Limitations and Difficulties 1406.5 Perspectives 142

Acknowledgments 143References 143

7 In Vivo Brain Imaging in Animal Models: A Focus on PET and MRI 149Fabien Chauveau, Mathieu Verdurand, and Luc Zimmer

7.1 Introduction: Role of Animal in In Vivo Imaging 1497.1.1 In Vivo Imaging as a Translational Approach for Basic Research 1497.1.2 In Vivo Imaging in Animal Models in the Pharmaceutical

Industry 1507.1.3 In Vivo Imaging in Animal Models and the 3R Principles 150

Contents jVII

7.2 The Choice of the Right Imaging Modality for Brain Imaging 1517.3 Small Animal Magnetic Resonance Imaging 1527.3.1 Principles 1527.3.2 Magnetic Resonance Spectroscopy 1527.3.3 Magnetic Resonance Imaging 1537.4 Positron Emission Tomography 1557.4.1 Basic Principles and Instrumentation 1557.4.2 PETand Neuronal Metabolism 1557.4.3 PETand Brain Receptors and Transporters 1567.4.4 PETand Receptor Occupancy 1587.4.5 PETand Neurotransmitter Release 1597.5 Clinical Translation: Limitations and Difficulties 1597.5.1 Anesthesia 1607.5.2 Spatial Resolution and Sensitivity 1607.5.3 The Mass Effect of Injected Tracers 1617.5.4 Multimodal PET–MRI for Better Clinical Translation 162

References 163

Part II Animal Models in Specific Disease Areas of Drug Discovery 167

8 Substance Abuse and Dependence 169Elena Martín-García, Patricia Robledo, Javier Guti�errez-Cuesta, andRafael Maldonado

8.1 Introduction 1698.2 Difficulties to Model Addiction in Animals 1708.3 Tolerance, Sensitization, and Physical Withdrawal 1728.3.1 Tolerance 1728.3.2 Sensitization 1738.3.3 Physical Manifestations of Withdrawal 1748.3.4 Affective Manifestations of Withdrawal 1758.4 Reward and Reinforcement 1778.4.1 Drug Discrimination 1778.4.2 Conditioned Place Preference 1788.4.3 Intracranial Self-Stimulation 1808.4.4 Self-Administration 1828.5 Translation to Clinics: Limitations and Difficulties 184

References 186

9 Mood and Anxiety Disorders 193Guy Griebel and Sandra Beesk�e

9.1 Introduction 1939.2 Animal Models of Anxiety Disorders 1949.2.1 Preclinical Measures of Anxiety 1949.2.2 Preclinical Anxiety Models and Endophenotypes 1959.3 Animal Models of Mood Disorders 197

VIIIj Contents

9.3.1 Major Depressive Disorder 1979.3.1.1 Preclinical Measures of Depression 1989.3.1.2 Endophenotype Models of Depression 1999.3.2 Bipolar Disorder 1999.4 Translation to Clinics: Limitations and Difficulties 200


10 Schizophrenia 207Ronan Depoort�ere and Paul Moser

10.1 Introduction 20710.2 Models Amenable to Use in Screening 20910.2.1 Models Based on the Use of Pharmacological Agents 20910.2.1.1 Dopaminergic Agonists 20910.2.1.2 NMDA/Glutamate Receptor Antagonists 21110.2.1.3 Other Pharmacological Agents Used to Induce Behavioural Changes 21210.2.1.4 5-HT2A Receptor Agonists 21210.2.1.5 Cannabinoid Receptor Agonists 21210.2.1.6 Muscarinic Receptor Antagonists 21310.2.1.7 Glycine B Receptor Antagonists 21310.2.2 Models Not Based on the Use of Pharmacological Agents 21310.2.2.1 Conditioned Avoidance Response 21310.2.2.2 Potentiation of PPI of the Startle Reflex 21410.2.3 Models More Time Consuming and/or Difficult to Implement 21410.2.3.1 Models Aimed at Reproducing More Complex Symptoms of

Schizophrenia 21410.2.3.2 Models Aimed at Reproducing the Chronic Nature of

Schizophrenia 21610.2.3.3 Models Based on Genetic Manipulations 21810.2.4 Models for Side Effects 21810.2.4.1 Models for Motor Side Effects 21910.2.4.2 Hyperprolactinemia 22010.2.4.3 Sedation and Motor Incoordination 22010.2.4.4 Models for Cognitive Side Effects 22010.2.4.5 Metabolic Disorders Models 22110.2.4.6 Models for Cardiovascular Effects 22110.3 Translation to the Clinic: Limitations and Difficulties 22110.3.1 Use of “Standard Subjects” 22110.3.2 From Here to . . . ? 222

References 223

11 Migraine and Other Headaches 231Inger Jansen-Olesen, Sarah Louise T. Christensen, and Jes Olesen

11.1 Introduction 23111.2 Vascular Models 231

Contents jIX

11.2.1 In Vitro 23211.2.2 In Vivo 23311.3 Neurogenic Inflammation 23411.4 Nociceptive Activation of the Trigeminovascular System 23411.4.1 Electrophysiological Recordings on Primary Dural Afferents in

Trigeminal Ganglion 23711.4.2 Electrophysiological Recordings in Trigeminal

Nucleus Caudalis 23911.4.3 Histological Markers after Nociceptive Stimulation of the

Trigeminovascular System 23911.5 Cortical Spreading Depression 24011.6 Human Experimental Migraine Provoking Models 24111.7 Animal Experimental Migraine Provoking Models 24211.8 Transgenic Models 24611.9 Behavioral Models 24611.9.1 Allodynia or Hyperalgesia 24711.9.2 Face Grooming 24811.9.3 Photophobia 24811.9.4 Various Behaviors 24911.10 Translation to Clinics: Limitations and Difficulties 249

References 250

12 Nociceptive, Visceral, and Cancer Pain 261Christophe Mallet, Denis Ardid, and David Balayssac

12.1 Introduction 26112.2 Acute Pain Tests 26112.2.1 Introduction 26112.2.2 Electrical Stimulus 26312.2.3 Thermal Stimulus 26412.2.4 Mechanical Stimulus 26412.2.5 Chemical Stimulus 26512.3 Visceral Pain Models 26512.3.1 Introduction 26512.3.2 Pain Achievement Test 26612.3.3 Animal Models 26712.3.4 Pathophysiology and Pharmacology 26912.4 Cancer Pain Models 27012.4.1 Introduction 27012.4.2 Pain Assessment in Animal Models of Cancer Pain 27012.4.3 Animal Models 27112.4.4 Pathophysiology and Pharmacology 27212.4.5 Conclusions 27212.5 Translation to Clinics: Difficulties and Limitations 27312.5.1 Acute Pain Tests 27312.5.2 Visceral Pain Models 274

Xj Contents

12.5.3 Cancer Pain Models 27412.5.4 Conclusions 275

References 275

13 Inflammatory, Musculoskeletal/Joint (OA and RA), andPostoperative Pain 283Laurent Diop and Yassine Darbaky

13.1 Introduction: Evaluation of Pain in Animal Models 28313.2 Inflammatory Pain 28713.2.1 Formalin Test 28713.2.2 Carrageenan-Induced Hyperalgesia 28713.2.3 Complete Freund’s Adjuvant-Induced Hyperalgesia 28813.2.4 Capsaicin-Induced Hyperalgesia 28813.3 Musculoskeletal/Joint Osteoarthritis (OA) and Rheumatoid

Arthritis (RA) Pain 28913.3.1 Osteoarthritis Pain Models 28913.3.2 Rheumatoid Arthritis Pain Models 29313.4 Postoperative Pain 29713.4.1 Incisional Pain 29813.4.2 Laparotomy 29913.4.3 Ovariohysterectomy 29913.4.4 Other Models of Postoperative Pain 29913.5 Translation to Clinics: Limitations and Difficulties 300

References 302

14 Neuropathic Pain 305Said M’Dahoma, Sylvie Bourgoin, and Michel Hamon

14.1 Introduction 30514.2 Main Types of Neuropathic Pain in Humans 30614.2.1 Neuropathic Pain Caused by Peripheral Nerve Lesions 30614.2.1.1 Diabetes-Induced Neuropathic Pain 30614.2.1.2 Human Immunodeficiency Virus-Related Pain 30614.2.1.3 Postherpetic Neuralgia 30714.2.1.4 Neuropathic Pain Caused by Anticancer Drugs 30714.2.2 Neuropathic Pain Caused by Central Lesions 30714.2.2.1 Spinal Cord Injury 30714.2.2.2 The Various Types of Pain in SCI Patients 30814.3 Modelization of Chronic Pain in Rodents 30914.3.1 Models of Peripheral Nerve Injury 30914.3.1.1 Nerve Section 30914.3.1.2 Nerve Ligation, Compression, and Other Lesion Procedures 31014.3.1.3 Drug- and Virus-Induced Neuropathic Pain 31414.3.2 Models of Spinal Cord Injury 31814.3.2.1 Spinal Cord Contusion 31814.3.2.2 Clip Compression Injury 319

Contents jXI

14.3.2.3 Spinal Cord Transection 31914.3.2.4 Spinal Cord Ischemia 31914.3.3 Neuropathic-Like Pain Evoked by Chemicals Administered

at the Spinal Level 32014.3.3.1 Intrathecal Administration of ATP 32014.3.3.2 Intrathecal Administration of BDNF 32014.3.3.3 Excitotoxic Injury to the Spinal Cord 32114.4 Translation to Clinics: Limitations and Difficulties 321

References 324

15 Obesity and Metabolic Syndrome 333Sunil K. Panchal, Maharshi Bhaswant, and Lindsay Brown

15.1 Introduction 33315.2 Why Metabolic Syndrome? 33315.3 Classical Animal Models of Obesity and Metabolic Syndrome 33515.3.1 Genetic Models of Obesity and Diabetes 33615.3.2 Artificially Induced Metabolic Syndrome in Animals 33715.3.2.1 Monosodium Glutamate-Induced Obesity 33815.3.2.2 Intrauterine Growth-Restricted Rats 33815.4 Human Experimental Models 34415.5 Translation to Clinics: Difficulties and Limitations 344

References 344

16 Cognitive Disorders: Impairment, Aging, and Dementia 349Nick P. van Goethem, Roy Lardenoije, Konstantinos Kompotis,Bart P.F. Rutten, Jos Prickaerts, and Harry W.M. Steinbusch

16.1 Introduction 34916.2 Pharmacological Models 34916.2.1 Inhibition of Energy/Glucose Metabolism 35016.2.2 Cholinergic Interventions 35016.2.3 Glutamatergic Antagonists 35216.2.4 Serotonergic Intervention 35316.3 Aging and Transgenic Models 35316.3.1 Normal Aging 35416.3.2 Alzheimer’s Disease 35516.3.3 Parkinson’s Disease 35816.3.4 Huntington’s Disease 35816.3.5 Frontotemporal Dementia 35916.3.6 Down Syndrome 36016.4 Translation to Clinics: Limitations and Difficulties 360

References 362

17 Stroke and Traumatic Brain Injury 367Dominique Lerouet, Val�erie C. Besson, and Michel Plotkine

17.1 Introduction 367

XIIj Contents

17.2 Stroke Models 36817.2.1 Global Stroke Models 36817.2.2 Focal Stroke Models 36917.2.2.1 Extravascular Models 36917.2.2.2 Photothrombosis Model 37017.2.2.3 Intraluminal Occlusion Model 37017.2.2.4 Thromboembolic Models 37017.3 Traumatic Brain Injury Models 37117.3.1 TBI Models with Craniotomy 37217.3.1.1 Weight-Drop Model 37217.3.1.2 Lateral Fluid Percussion Model 37217.3.1.3 Controlled Cortical Impact Model 37217.3.2 TBI Models without Craniotomy 37217.3.2.1 Weight-Drop Model 37317.3.2.2 Impact/Acceleration Model 37317.3.2.3 Acceleration/Deceleration Model 37317.3.3 Blast Injury Models 37317.3.4 Repetitive TBI Models 37417.4 Outcome Assessment 37517.5 Translation to Clinics: Limitations and

Difficulties 37717.5.1 The Actual Target: From the Neuron to the Neurogliovascular

Unit 37717.5.2 From Bench to Bedside to Bench: Recommendations

for Improving the Translational Research 378References 379

18 Movement Disorders: Parkinson’s Disease 387Houman Homayoun and Christopher G. Goetz

18.1 Introduction 38718.1.1 Parkinson’s Disease 38718.2 Drug- and Toxin-Based Models of PD 38918.2.1 Reserpine 38918.2.2 Haloperidol 39018.2.3 6-OHDA 39018.2.4 MPTP 39318.2.5 Rotenone 39618.2.6 Paraquat and Other Environmental Toxins 39818.3 Genetic and Functional Models of PD 39818.3.1 Rodent Genetic Models 39918.3.1.1 Adult-Onset Rodent Gene-Based Models 40118.3.2 Rodent Function-Based Models 40318.3.3 Nonrodent Genetic Models of PD 40418.4 Translation to Clinics: Limitations and Difficulties 405

References 409

Contents jXIII

19 Epilepsy: Animal Models to Reproduce Human Etiopathology 415Isabelle Guillemain, Christophe Heinrich, and Antoine Depaulis

19.1 Introduction 41519.2 What Animal Species to Use to Model Epilepsy? 41619.3 Which Type of Models Provide the Most Reliable Information on the

Pathophysiology of Epilepsies? 41719.4 Modeling Four Prototypic Forms of Epilepsy 41819.4.1 Idiopathic Generalized Epilepsies with Convulsive Seizures 41819.4.2 Idiopathic Generalized Epilepsies with Absence Seizures 41919.4.3 Focal Epilepsies Associated with Cortical Dysplasia 42019.4.4 Modeling Focal Epilepsies Associated with Hippocampal Sclerosis 42219.5 Translation to Clinics: Limitations and Difficulties 423

References 425

20 Lung Diseases 431Laurent Boyer, Armand Mekontso-Dessap, Jorge Boczkowski,and Serge Adnot

20.1 Introduction 43120.2 Animal Models of Lung Emphysema or Chronic Obstructive

Pulmonary Disease 43220.2.1 Cigarette Smoke-Induced COPD 43220.2.2 COPD Induced by Tracheal Elastase Instillation 43320.2.3 Genetically Modified Models of COPD 43420.2.4 Conclusions 43420.3 Animal Models of Pulmonary Hypertension 43420.3.1 Relevance of Experimental Animal Models of PH to Human PH 43520.3.2 The Monocrotaline Model of Pulmonary Hypertension 43620.3.3 Fawn-Hooded Rats 43720.3.4 Hypoxic PH 43720.3.5 SU5416 Treatment Combined with Hypoxia in Mice 43820.3.6 PH Related to COPD or Smoke Exposure 43920.4 Animal Models of Fibrotic Lung Diseases 43920.4.1 Bleomycin-Induced Pulmonary Fibrosis 43920.4.2 Other Models 44020.5 Animal Models of Acute Respiratory Distress Syndrome 44020.6 Translation to Clinics: Limitations and Difficulties 445

References 446

21 Heart Failure 449Jin Bo Su and Alain Berdeaux

21.1 Introduction 44921.2 Hypertension-Related Heart Failure 45021.3 Pressure and Volume Overload-Induced Heart Failure 45221.3.1 Pressure Overload-Induced Heart Failure 45221.3.2 Volume Overload-Induced Heart Failure 454

XIVj Contents

21.3.3 Double Pressure and Volume Overload-Induced Heart Failure 45421.4 Toxic Molecule-Induced Heart Failure 45521.4.1 Adriamycin-Induced Heart Failure in Rats 45521.4.2 Monocrotaline-Induced Right Ventricular Heart Failure 45521.5 Heart Failure Models Related to Myocardial Ischemia and/or

Myocardial Infarction 45621.5.1 Myocardial Ischemia and/or Myocardial Infarction 45621.5.2 Coronary Microembolization-Induced Heart Failure 45721.6 Pacing-Induced Heart Failure 45821.7 Gene Mutation-Induced Cardiomyopathies 46021.7.1 Cardiomyopathic Hamsters 46021.7.2 Golden Retriever Muscular Dystrophy Dogs 46021.7.3 Genetic Modification-Induced Cardiomyopathies in Mice 46121.8 Translation to Clinics: Limitations and Difficulties 462

References 462

22 Endocrine Disorders 473Thomas Cuny, Anne Barlier, and Alain Enjalbert

22.1 Introduction 47322.2 Animal Models in Autoimmune Endocrine Diseases 47422.2.1 Animal Models of Autoimmune Thyroiditis 47422.2.2 Animal Models for Addison’s Disease 47622.2.3 Animal Models for Other Endocrine Autoimmune

Diseases 47622.3 Animal Models in Endocrine Tumors 47722.3.1 Multiple Endocrine Neoplasia Syndromes 47722.3.2 Adrenal Tumorigenesis 47822.3.3 Thyroid Tumorigenesis 48122.3.4 Pituitary Tumorigenesis 48222.4 Animal Models in Endocrine Physiology: Organogenesis,

Reproduction, and Metabolism 48522.4.1 Pituitary Development Disorders: Lessons from

Animal Models 48522.4.2 Animal Models and Reproductive Function 48722.4.3 Animal Models Used in Calcium Homeostasis Studies 48922.5 Translation to Clinics: Limitations and Difficulties 490

References 491

23 Gastrointestinal Disorders: A Patho-biotechnology Approach toProbiotic Therapy 497Roy D. Sleator

23.1 Introduction 49723.2 Delivery: Improving Probiotic Resistance to Process-Induced Stresses

and Storage Conditions 49823.3 Survival: Improving Probiotic–Host Colonization 500

Contents jXV

23.4 Efficacy: “Designer Probiotics” 50023.5 Translation to Clinics: Limitations and Difficulties 501


24 Renal Disorders 505Dominique Guerrot, Christos Chatziantoniou, and Jean-Claude Dussaule

24.1 Introduction 50524.2 Animal Models 50624.2.1 The RenTg Model of CKD 50724.2.1.1 Benefits of the RenTg Model 50924.2.2 Unilateral Ureteral Obstruction 51024.2.2.1 Technical Aspects 51024.2.2.2 Pathology and Pathophysiology 51124.2.2.3 Clinical Relevance and Limits 51124.2.3 Renal Ischemia–Reperfusion 51124.2.3.1 Technical Aspects 51224.2.3.2 Pathology and Pathophysiology 51224.2.3.3 Clinical Relevance and Limits 51324.2.4 Experimental Alloimmune Glomerulonephritis 51324.2.4.1 Technical Aspects 51324.2.4.2 Pathology and Pathophysiology 51424.2.4.3 Clinical Relevance and Limits 51424.2.5 Angiotensin II-Mediated Hypertensive Nephropathy 51424.2.5.1 Technical Aspects 51524.2.5.2 Pathology and Pathophysiology 51524.2.5.3 Clinical Relevance and Limits 51624.2.6 L-NAME-Mediated Hypertensive Nephropathy 51624.2.6.1 Technical Aspects 51624.2.6.2 Pathology and Pathophysiology 51624.2.6.3 Clinical Relevance and Limits 51724.3 Translation to Clinics: Limitations and Difficulties 518

References 518

25 Genitourinary Disorders: Lower Urinary Tract andSexual Functions 523Pierre Cl�ement, Delphine Behr-Roussel, and FranScois Giuliano

25.1 Introduction 52325.2 Lower Urinary Tract Function 52325.2.1 Physiology of Micturition 52425.2.2 Investigation of Lower Urinary Tract Function 52425.2.2.1 Cystometry Evaluation 52425.2.2.2 Evaluation of Urethral Function 52525.2.2.3 Bladder Afferent Recording 52625.2.3 Pathophysiological Models 527

XVIj Contents

25.2.3.1 Bladder Outlet Obstruction 52725.2.3.2 Overactive Bladder 52725.2.3.3 Neurogenic Detrusor Overactivity 52825.2.3.4 Painful Bladder Syndrome/Interstitial Cystitis 52825.3 Sexual Functions 52925.3.1 Physiology of Female and Male Sexual Response 52925.3.2 Models for Sexual Behavior 53025.3.2.1 Sexual Preference Paradigms 53025.3.2.2 Copulatory Tests 53125.3.3 Investigation of the Peripheral Female Sexual Response 53225.3.4 Investigation of Erection 53225.3.4.1 Penile Reflex 53225.3.4.2 Erection in Conscious Animals 53325.3.4.3 Intracavernosal Pressure Measurement 53325.3.4.4 Pharmacologically Induced Erection 53425.3.4.5 Neurally Evoked Erection 53425.3.5 Investigation of Ejaculation 53425.3.5.1 Physiological Markers of Emission and Expulsion Phases 53425.3.5.2 Pharmacologically Induced Ejaculation 53525.3.5.3 Lumbar Spinothalamic Neurons Electrical Stimulation 53525.3.5.4 Expulsion Spinal Reflex 53525.3.6 Pathophysiological Models 53625.3.6.1 Female Sexual Dysfunctions 53625.3.6.2 Erectile Dysfunction 53625.3.6.3 Ejaculatory Disorders 53825.4 Translation to Clinics: Difficulties and Limitations 538

References 540

Index 543

Contents jXVII

List of Contributors

Serge AdnotUniversit�e Paris-Est Cr�eteil (UPEC)Facult�e de M�edecineHopital Henri Mondor51 Avenue du Mar�echal de Lattre deTassigny94010 Cr�eteil CedexFrance

Denis ArdidClermont Universit�e (Universit�ed’Auvergne)NEURO-DOLFaculté de médecinePlace Henri Dunant63000 Clermont-FerrandFrance

and

INSERM U110763001 Clermont-FerrandFaculté de médecinePlace Henri DunantFrance

David BalayssacClermont Universit�e (Universit�ed’Auvergne)NEURO-DOL63000 Clermont-FerrandFrance

and

INSERM U110763001 Clermont-FerrandFaculté de médecinePlace Henri DunantFrance

and

CHU Clermont-FerrandToxicoloy department63003 Clermont-FerrandFrance

Anne BarlierAP-HM, ConceptionLaboratory of Molecular Biology147 Bd Baille13855 Marseille CedexFrance

and

Aix-Marseille UniversityFacult�e de M�edecine NordLaboratoire CRN2M, UMR 7286CNRS51 Bd Pierre Dramard13344 Marseille Cedex 15France

jXIX

Sandra Beesk�eSanofiExploratory Unit1 avenue Pierre Brossolette91385 Chilly-MazarinFrance

Delphine Behr-RousselPelvipharm Laboratories2, avenue de la source de la Bièvre78390 Montigny le BretonneuxFrance

and

University of Versailles-St Quentinen YvelinesSchool of Health SciencesSIRIUS/EA45012, avenue de la source de la Bièvre78390 Montigny le BretonneuxFrance

Alain BerdeauxUniversit�e Paris-Est Cr�eteil (UPEC)Facult�e de M�edecineLaboratoire de PharmacologieINSERM U955 (�equipe 3 IMRB)Rue du G�en�eral Sarrail, 894010 Cr�eteil CedexFrance

Val�erie C. BessonUniversit�e Paris DescartesFacult�e de PharmacieLaboratoire de PharmacologieEA 4475 “Pharmacologie de laCirculation C�er�ebrale”4, avenue de l’Observatoire75006 Paris Cedex 06France

Maharshi BhaswantVictoria UniversityCollege of Health & BiomedicineSt Albans, Melbourne 3021Australia

Jorge BoczkowskiUniversit�e Paris-Est Cr�eteil (UPEC)Facult�e de M�edecineHopital Henri Mondor51 Avenue du Mar�echal de Lattre deTassigny94010 Cr�eteil CedexFrance

Sylvie BourgoinUniversit�e Pierre et Marie CurieFaculty of MedicineNeuropsychopharmacology UnitINSERM U894 – CPNsite Piti�e-Salpetri�ere91, boulevard de l’Hopital75634 Paris Cedex 13France

Laurent BoyerUniversit�e Paris-Est Cr�eteil (UPEC)Facult�e de M�edecineHopital Henri Mondor51 Avenue du Mar�echal de Lattrede Tassigny94010 Cr�eteil CedexFrance

V�eronique BraultUniversit�e de StrasbourgInstitut Clinique de la SourisICS-MCI, PHENOMIN, GIE CERBMCNRS, INSERM1 rue Laurent Fries67404 IllkirchFrance

XXj List of Contributors

and

Universit�e de StrasbourgInstitut de G�en�etique BiologieMol�eculaire et CellulaireIGBMC, GIE CERBMCNRS, INSERMUMR7104, UMR9641 rue Laurent Fries67404 IllkirchFrance

Lindsay BrownUniversity of Southern QueenslandSchool of HealthNursing and MidwiferyToowoomba, Queensland 4350Australia

Christos ChatziantoniouInserm UMR S 1155Sorbonne UniversitésUPMC Univ Paris 064 rue de la Chine75020 ParisFrance

and

Universit�e Pierre et Marie CurieParisFrance

Fabien ChauveauUniversité Lyon 1Lyon Neuroscience Research CenterCNRS, INSERM59 Bd Pinel69003 LyonFrance

and

CERMEP-Imagerie du VivantLyonFrance

Sarah Louise T. ChristensenUniversity of CopenhagenFaculty of Health SciencesGlostrup HospitalDepartment of Neurology andGlostrup Research InstituteDanish Headache CenterNordre Ringvej 572600 GlostrupDenmark

Pierre ClémentPelvipharm Laboratories2, avenue de la source de la Bièvre78390 Montigny le BretonneuxFrance

and


Thomas CunyUniversity Hospital of Nancy-BraboisDepartment of Endocrinology andMedical GynaecologyRue du Morvan54511 Vandoeuvre-Les-Nancy CedexFrance

List of Contributors jXXI

and


Yassine DarbakyANS BiotechFacult�e de M�edecine et dePharmacologie28, place Henri Dunant63000 Clermont-FerrandFrance

Antoine DepaulisINSERM U836Dynamics of Epileptic SynchronousNetworks38042 Grenoble Cedex 9France

and

Universit�e Joseph FourierGrenoble Institut des Neurosciences38042 Grenoble Cedex 9France

Ronan Depoort�ereCentre de Recherche Pierre-FabreNeuropsychopharmacology Unit17 avenue Jean Moulin81106 CastresFrance

Laurent DiopANS BiotechFacult�e de M�edecine et dePharmacologie28, place Henri Dunant63000 Clermont-FerrandFrance

Jean-Claude DussauleInserm UMR S 1155Sorbonne UniversitésUPMC Univ Paris 064 rue de la Chine75020 ParisFrance

and

Saint-Antoine HospitalHUEP, AP-HPDepartment of Physiology184 rue du faubourg Saint-Antoine,75012 ParisFrance

Alain EnjalbertAP-HM, ConceptionLaboratory of Molecular Biology147 Bd Baille13855 Marseille CedexFrance

and


FranScois GiulianoPelvipharm Laboratories2, avenue de la source de la Bièvre78390 Montigny le BretonneuxFrance

XXIIj List of Contributors

and


and

Raymond Poincar�e HospitalDepartment of Physical Medicineand RehabilitationNeuro-Uro-AndrologyAP-HP104, boulevard Raymond Poincaré92380 GarchesFrance

Christopher G. GoetzRush University Medical CenterDepartment of Neurology1725 West Harrison StreetChicago, IL 60612USA

Guy GriebelSanofiExploratory Unit1 avenue Pierre Brossolette91385 Chilly-MazarinFrance

Dominique GuerrotINSERM Unit 1096Rouen University Medical School22 Boulevard Gambetta76183 RouenFrance

and

Rouen University HospitalDepartment of Nephrology1 rue de Germont76031 RouenFrance

Isabelle GuillemainINSERM U836Dynamics of Epileptic SynchronousNetworks38042 Grenoble Cedex 9France

and


Javier Guti�errez-CuestaUniversitat Pompeu FabraLaboratori de NeurofarmacologiaParc de Recerca Biomedica deBarcelona (PRBB)Dr. Aiguader 8808003 BarcelonaSpain

Antonio Guzm�anEsteveDepartment of ToxicologyDrug Discovery & PreclinicalDevelopmentParc Cientific BarcelonaBaldiri Reixac 4–808028 BarcelonaSpain

List of Contributors jXXIII

Michel HamonUniversit�e Pierre et Marie CurieFaculty of MedicineNeuropsychopharmacology UnitINSERM U894 – CPNsite Piti�e-Salpetri�ere91, boulevard de l’Hopital75634 Paris Cedex 13France

Christophe HeinrichINSERM U836Dynamics of Epileptic SynchronousNetworks38042 Grenoble Cedex 9France

and


Yann H�eraultUniversit�e de StrasbourgInstitut Clinique de la SourisICS-MCI, PHENOMIN, GIE CERBMCNRS, INSERM1 rue Laurent Fries67404 IllkirchFrance

and

Universit�e de StrasbourgInstitut de G�en�etique BiologieMol�eculaire et CellulaireIGBMC, GIE CERBMCNRS, INSERMUMR7104, UMR9641 rue Laurent Fries67404 IllkirchFrance

and

Transgen�ese et Archivage d’AnimauxMod�elesTAAM UPS44, CNRS, PHENOMIN3B rue de la F�erollerie45071 Orl�eans Cedex 2France

Houman HomayounUniversity of PittsburghMedical CenterDepartment of Neurology3471 Fifth Ave, suite 810Pittsburgh, PA 15213USA

Inger Jansen-OlesenUniversity of CopenhagenFaculty of Health SciencesGlostrup HospitalDepartment of Neurology andGlostrup Research InstituteDanish Headache CenterNordre Ringvej 572600 GlostrupDenmark

Konstantinos KompotisMaastricht UniversitySchool for Mental Health andNeuroscienceDepartment of NeuroscienceUniversiteitssingel 506229 ER MaastrichtThe Netherlands

XXIVj List of Contributors

Roy LardenoijeMaastricht UniversitySchool for Mental Health andNeuroscienceDepartment of NeuroscienceUniversiteitssingel 506229 ER MaastrichtThe Netherlands

Dominique LerouetUniversit�e Paris DescartesFacult�e de PharmacieLaboratoire de PharmacologieEA 4475 “Pharmacologie de laCirculation C�er�ebrale”4, avenue de l’Observatoire75006 Paris Cedex 06France

Rafael MaldonadoUniversitat Pompeu FabraDepartment of Experimental &Health SciencesLaboratory of Neuropharmacology(NeuroPhar)Barcelona Biomedical Research Park(PRBB)Dr. Aiguader 8808003 BarcelonaSpain

Christophe MalletClermont Universit�e (Universit�ed’Auvergne)NEURO-DOLFaculté de médecinePlace Henri Dunant63000 Clermont-FerrandFrance

and

INSERM U1107Faculté de médecinePlace Henri Dunant63001 Clermont-FerrandFrance

Elena Martín-GarcíaUniversitat Pompeu FabraLaboratori de NeurofarmacologiaParc de Recerca Biomedica deBarcelona (PRBB)Dr. Aiguader 8808003 BarcelonaSpain

Said M’DahomaUniversit�e Pierre et Marie CurieFaculty of MedicineNeuropsychopharmacology UnitINSERM U894 – CPNsite Piti�e-Salpetri�ere91, boulevard de l’Hopital75634 Paris Cedex 13France

Armand Mekontso-DessapUniversit�e Paris-Est Cr�eteil (UPEC)Hopital Henri MondorService de R�eanimation M�edicaleAP-HP94010 Cr�eteil CedexFrance

Paul MoserCentre de Recherche Pierre-FabreNeuropsychopharmacology Unit17 avenue Jean Moulin81106 CastresFrance

List of Contributors jXXV

Jes OlesenUniversity of CopenhagenFaculty of Health SciencesGlostrup HospitalDepartment of Neurology andGlostrup Research InstituteDanish Headache CenterNordre Ringvej 572600 GlostrupDenmark

Sunil K. PanchalUniversity of Southern QueenslandCentre for Systems BiologyToowoomba, Queensland 4350Australia

Guillaume PavlovicUniversit�e de StrasbourgInstitut Clinique de la SourisICS-MCI, PHENOMIN, GIE CERBMCNRS, INSERM1 rue Laurent Fries67404 IllkirchFrance

Michel PlotkineUniversit�e Paris DescartesFacult�e de PharmacieLaboratoire de PharmacologieEA 4475 “Pharmacologie de laCirculation C�er�ebrale”4, avenue de l’Observatoire75006 Paris Cedex 06France

Jos PrickaertsMaastricht UniversitySchool for Mental Health andNeuroscienceDepartment of NeuroscienceUniversiteitssingel 506229 ER MaastrichtThe Netherlands

Patricia RobledoUniversitat Pompeu FabraLaboratori de NeurofarmacologiaParc de Recerca Biomedica deBarcelona (PRBB)Dr. Aiguader 8808003 BarcelonaSpain

and

IMIM-Hospital del Mar ResearchInstituteHuman Pharmacology and ClinicalNeurosciences Research GroupNeurosciences Research ProgrammePRBBCalle Dr. Aiguader 8808003 BarcelonaSpain

Luz RomeroEsteveDrug Discovery & PreclinicalDevelopmentParc Cientific BarcelonaBaldiri Reixac 4–808028 BarcelonaSpain

XXVIj List of Contributors

Bart P.F. RuttenMaastricht UniversitySchool for Mental Health andNeuroscienceDepartment of NeuroscienceUniversiteitssingel 506229 ER MaastrichtThe Netherlands

David Sabat�eEsteveR&D Department Animal HealthDivisionAnimal Ethics CommitteeAvinguda Mare de D�eu deMontserrat, 22108041 BarcelonaSpain

Roy D. SleatorCork Institute of TechnologyDepartment of Biological SciencesRossa AvenueBishopstown, CorkIreland

Tania SorgUniversit�e de StrasbourgInstitut Clinique de la SourisICS-MCI, PHENOMIN, GIE CERBMCNRS, INSERM1 rue Laurent Fries67404 IllkirchFrance

Harry W.M. SteinbuschMaastricht UniversitySchool for Mental Health andNeuroscienceDepartment of NeuroscienceUniversiteitssingel 506229 ER MaastrichtThe Netherlands

and

Maastricht UniversitySchool for Mental Health andNeuroscienceDepartment of NeuroscienceUniversiteitssingel 506229 ER MaastrichtThe Netherlands

Jin Bo SuUniversit�e Paris-Est Cr�eteil (UPEC)Facult�e de M�edecineLaboratoire de PharmacologieINSERM U955 (�equipe 3 IMRB)Rue du G�en�eral Sarrail, 894010 Cr�eteil CedexFrance

Nick P. van GoethemMaastricht UniversitySchool for Mental Health andNeuroscienceDepartment of NeuroscienceUniversiteitssingel 506229 ER MaastrichtThe Netherlands

Jos�e Miguel VelaEsteveDrug Discovery & PreclinicalDevelopmentParc Cientific BarcelonaBaldiri Reixac 4–808028 BarcelonaSpain

Mathieu VerdurandUniversité Lyon 1Lyon Neuroscience Research CenterCNRS, INSERM59 Bd Pinel, 69003 LyonFrance

List of Contributors jXXVII

and

CERMEP-Imagerie du VivantLyonFrance

Luc ZimmerUniversité Lyon 1Lyon Neuroscience Research CenterCNRS, INSERM59 Bd Pinel, 69003 LyonFrance

and

CERMEP-Imagerie du Vivant59 Bd Pinel, 69003 LyonFrance

and

Hospices Civils de LyonGroupement Hospitalier Est59 Bd Pinel, 69003 LyonFrance

XXVIIIj List of Contributors

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