Front Cover

Providing Pharmacological Access to the Brain: Alternate Approaches

Copyright Page

Table of Contents

Contributors to Volume 21

Preface

Methods in Neurosciences

Section I: Characterizing the Blood-Brain Barrier

Chapter [1]. Cellular Response of Central Nervous System Tissue to Invasive Therapeutic Measures

Introduction

Definition of Cellular Response to Injury

Definition of Trophic Mechanisms of Injury Response

Models for Therapeutic Manipulation

Efficacy of Therapeutic Measures

Efficacy of Therapeutic Measures

Conclusions

References

Chapter [2]. Models of Angiogenesis and the Blood-Brain Barrier

Introduction

Techniques for Localization of Proliferating Vasculature (Angiogenesis)

Strategies for Determining Temporal Sequence and Source of Neovascularization in Neural Transplants

Techniques to Determine Blood-Brain Barrier Permeability

Acknowledgments

References

Section II: Transiently Removing the Blood-Brain Barrier

Chapter [3]. Osmotic Opening of the Blood-Brain Barrier and Brain Tumor Chemotherapy

Introduction

Osmotic Opening of Blood-Brain Barrier

Size Dependence of Blood-Brain Barrier Permeability

Osmotic Opening and Brain Tumor Chemotherapy

Conclusions

References

Chapter [4]. Osmotic Blood-Brain Barrier Modification: Increasing Delivery of Diagnostic and Therapeutic Agents to the Brain

Introduction

Blood-Brain Barrier

Blood-Brain Barrier Disruption

Development of Animal Models

Confirming Blood-Brain Barrier Disruption

Factors Influencing Successful Blood-Brain Barrier Disruption and Agent Delivery

Conclusion

References

Section III: Facilitated Transport through the Blood-Brain Barrier

Chapter [5]. Peripheral Administration of Nerve Growth Factor Conjugated to an Anti-transferrin Receptor Antibody Increases Cholinergic Neuron Survival in Intraocular Forebrain Transplants

Introduction

Methods and Results

Concluding Remarks

Acknowledgments

References

Chapter [6]. Ferrotransferrin and Antibody against the Transferrin Receptor as Potential Vehicles for Drug Delivery across the Mammalian Blood-Brain Barrier into the Central Nervous System

Introduction

Iron, Transferrin, and Transferrin Receptor

Preparation and Application of Ferrotransferrin and Antibody against the Ferrotransferrin Receptor

Analyses of Potential Transcytosis of Blood-Borne, Receptor-Mediated Probe Molecules across the Blood-Brain Barrier

Transendothelial Pathways for Ferrotransferrin and Antibody against the Ferrotransferrin Receptor as Vehicles for Circumventing the Blood-Brain Barrier

Summary and Conclusions

Acknowledgments

References

Chapter [7]. DepoFoam-Mediated Drug Delivery into Cerebrospinal Fluid

Introduction

Synthesis of DepoFoam-Encapsulated Ara-C (DTC 101)

Preparation of DepoFoam-Encapsulated Methotrexate (Depo/MTX)

Preparation of Depo/Morphine

Synthesis of Depo/IFN

Central Nervous System Pharmacokinetic Analysis

Intraventricular Pharmacokinetics of DTC 101 in Rats

Intralumbar Pharmacokinetics of DTC 101 in Monkeys

Intracisternal Pharmacokinetics with Depo/MTX in Rats

Intraventricular Pharmacokinetics of DTC 101 in Humans

Summary

Acknowledgments

References

Section IV: Polymeric Release Systems for the Central Nervous System

Chapter [8]. Interstitial Drug Delivery to the Central Nervous System Using Controlled Release Polymers: Chemotherapy for Brain Tumors

Introduction

Methods

Results

Conclusions

References

Chapter [9]. Sustained Intracerebral Delivery of Nerve Growth Factor with Biodegradable Polymer Microspheres

Introduction

Methods

Results

Summary

Acknowledgments

References

Chapter [10]. Polymerie Drug Carrier Systems in the Brain

Introduction

Polymers for Drug Delivery

Nondegradable Implants for Treatment of Brain Cancer

Biodegradable Implants for Treatment of Brain Cancer

Delivery of Neurotransmitters and Neuromodulators

Concluding Remarks

References

Section V: Using Pump Delivery Devices within the Brain

Chapter [11]. Using Osmotic Minipumps for Intracranial Delivery of Amino Acids and Peptides

Intracerebroventricular Injection versus Microinjection into Brain

Minipump Delivery Systems

Practical Considerations for Cannulation and Minipump Use

Summary

Acknowledgments

References

Chapter [12]. Continuous Central Nervous System Infusion with Alzet Osmotic Pumps

Introduction

Construction of Infusion Devices

Preimplantation Preparation of Pumps and Infusion Devices

Infusion/Treatment Protocols

Stereotaxic Surgery

Experimental Examples

Conclusion

Acknowledgments

References

Chapter [13]. Injection of Biologically Active Substances into the Brain

Introduction

Getting Started

Preparing Guide Cannula and Stylet

Inserting Guide Cannula-Stylet Assembly

Injecting Solutions

Injecting Solutions into Ventricular System

Unilateral 6-Hydroxydopamine Lesions

Injection of Cells into Brain Parenchyma

Acknowledgments

References

Section VI: Using Implanted Living Tissues within the Brain

Chapter [14]. Factors Important in the Survival of Dopamine Neurons in Intracerebral Grafts of Embryonic Substantia Nigra

Introduction

Nigral Grafts

Use of Cell Suspensions and Vital Stains

Use of in Vitro Cultures

In Vivo Intracerebral Grafts

Conclusions

Acknowledgments

References

Chapter [15] Techniques in Adrenal Medullary Transplantation for Experimental Nonhuman Primate Parkinsonism

Adrenalectomy in Nonhuman Primate

Peripheral Nerve Harvesting in Nonhuman Primate

Striatal Grafting and Cografting for Nonhuman Primate Parkinsonian Syndromes

Concluding Remarks

Acknowledgments

References

Chapter [16]. Technical Aspects of Transplantation of the Adrenal Medulla to the Caudate Nucleus as a Treatment for Parkinson's Disease

Introduction

Overview of Procedure

Preparation of Adrenal Medulla

Conclusions

References

Section VII: Creating Cell Lines for Transplant Therapies

Chapter [17]. Transplantation of Epidermal Growth Factor-Responsive Neural Stem Cell Progeny into the Murine Central Nervous System

Introduction

Production and in Vitro Characterization of Epidermal Growth Factor-Responsive Neural Stem Cells

Identification of Stem Cell Progeny and Their Differentiation Potential in Vitro

Formation of Myelinating Oligodendrocytes by Epidermal Growth Factor-Responsive Stem Cell Progeny when Transplanted in Vivo

Differentiation and Survival of Epidermal Growth Factor-Responsive Stem Cells, Genetically Tagged with Escherichia coli ß-Galactosidase Gene, When Implanted into Mouse Cerebral Cortex

Transgenic Mouse-Derived Neural Stem Cells: A Source of Marked Glial Cells for Central Nervous System Transplantation

Conclusions

Acknowledgments

References

Chapter [18]: Application of Astrocyte Transplants as a Therapeutic Intervention

Introduction

Methodological Considerations for Implantation

Preparation and Implantation of Astrocytes into Brain

Characterization of Astrocyte Implants

Summary

References

Chapter [19]. Development of Immortalized Cell Lines for Transplantation in Central Nervous System Injury and Degeneration Models

Introduction

General Guidelines

Establishment of Immortalized Cell Line

Selection and Characterization

Differentiation

Cell Labeling

Transplantation

Conclusions

References

Section VIII: Using Implanted Living Cells within the Central Nervous System

Chapter [20]. Use of Genetically Modified Cells to Deliver Neurotrophic Factors and Neurotransmitters to the Brain

Introduction

In Vitro Development and Characterization of Engineered Cells

In Vivo Characterizations of Engineered Cells

Summary

Acknowledgments

References

Chapter [21]. Neuropeptide and Catecholamine Delivery to Central Nervous System by Implanted Chromaffin Cells

Introduction

Graft Preparations

Spinal Subarachnoid Grafts

Intraparenchymal Grafts

Conclusions

Acknowledgment

References

Section IX: Using Implanted Encapsulated Cells within the Brain

Chapter [22]. Microencapsulation of Cells in Thermoplastic Copolymer (Hydroxyethyl Methacrylate-Methyl Methacrylate)

Introduction

Materials and Methods

Illustrative Results

Conclusions

Acknowledgments

References

Chapter [23]. Hydrogel Applications for Encapsulated Cellular Transplants

Introduction

Cellular Preparations

Matrix Preparations

Microencapsulation Process

Macroencapsulation

Assessment

Concluding Remarks

Acknowledgments

References

Chapter [24]. Tests for Validating the Safety of Encapsulated Xenografts

Introduction

Xenogeneic Cells in Transplants

Tests for Uniformity of Immunoisolation Devices

Qualitative Issues

Quantitative Issues

Testing, Implanting, and Removing Devices

Conclusion

References

Section X: Induced Gene Expression in Intrinsic Central Nervous System Cells with DNA Injected into the Brain

Chapter [25]. Particle Bombardment for Gene Transfer into Nerve Cell Systems

Introduction

Accell Gene Transfer Technique

Application to Central Nervous System Primary Cultures and Cell Expiants

Application to Mammalian Somatic Tissues in General

Summary

Acknowledgment

References

Section XI: Viral Transfection of Intrinsic Cells within the Brain

Chapter [26]. A Defective Herpes Simplex Virus Vector System for Genetic Intervention in the Adult Brain: Applications to Gene Therapy and Neuronal Physiology

Introduction: Genetic Intervention in Brain

Strategies for Manipulation of Neuronal Physiology by Genetic Intervention

Gene Therapy Approaches with HSV-1 Vectors

Defective HSV-1 Vector System for Gene Transfer into Neuronal Cells

Alteration of Neuronal Physiology by Expression of Unregulated Adenylate Cyclase in Neurons

Summary

References

Chapter [27]. Expression of Neurotrophic Genes from Herpes Simplex Virus Type 1 Vectors: Modifying Neuronal Phenotype

Introduction

Amplicon Vector System

Packaging of Defective HSV-1 Viral Vectors

Specifics about Packaging Procedure

Analysis of Viral Stocks

Troubleshooting

Viral Transduction

Other Viral Vectors Systems

Safety and Other Issues Related to Vector Use

Summary

Acknowledgments

References

Section XII: Predicting the Future of Central Nervous System Delivery System Technologies

Chapter [28]. Assessing Commercial Potential of Central Nervous System Delivery Approaches

Introduction

Assessing Market Size and Value

Identifying Key Issues for Analysis

Identifying Competitive Therapeutic, Economic, and Societal Advantages

Ranking Therapeutic Approaches

Predicting Breakthroughs

Additional Assessments

Conclusion

References

Index

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