Front Cover

Adenosine Receptors in Neurodegenerative Diseases

Copyright Page

Dedication

Contents

List of Contributors

Foreword and History of Adenosine in the Central Nervous System

References

Acknowledgments

I. Physiology

1 Adenosine Receptor Biology in the Central Nervous System

Sources of Adenosine in the CNS

Receptor Subtypes and Their CNS Distribution

A1 Adenosine Receptors

A2A Adenosine Receptors

A2B Adenosine Receptors

A3 Adenosine Receptors

Crosstalk With Other Receptors

Adenosine and CNS Diseases

Recent Clinical Trials

A1 Adenosine Receptors

A2A Adenosine Receptors

A2B Adenosine Receptors

A3 Adenosine Receptors

References

2 Adenosine Signaling Throughout Development

Introduction

Effects of Adenosine Signaling and Its Dysfunction in CNS

Effects of Adenosine in Oligodendrocytes Development

Effects of Adenosine on Cardiovascular System During Embryogenesis

Postnatal Effects of Adenosine on Cardiovascular System

Postnatal Effect of Adenosine on Respiratory System

Use of Methylxanthines in Premature Babies

Postnatal Effects of Adenosine on the Genitourinary System

Postnatal Effect of Adenosine on the Enteric System

Postnatal Effect of Adenosine on Other Systems

Conclusion

References

3 Influence of Adenosine on Synaptic Excitability

Introduction

Molecular & Physiological Mechanisms

Influence on Neurotransmitter Availability and Basal Synaptic Transmission

Adenosine Tunes the Responses of Postsynaptic Glutamate and GABA Receptors

Astrocyte-Derived Adenosine Controls Basal Synaptic Transmission and the Available Range for Plasticity Control

Metamodulation by Adenosine: Impact on Synaptic Plasticity

Adenosine Shapes Synapses for Plasticity

Implications for Epilepsy

Pathophysiological Mechanisms

Adenosine Receptor-Dependent Effects

Adenosine Receptor-Independent Effects

Disruption of Adenosine Homeostasis in Epilepsy

Comorbidities of Epilepsy

Therapeutic Implications

Conclusions and Outlook

Acknowledgments

References

4 Regulation of Synaptic Transmission by Adenosine at the Neuromuscular Junction

Introduction

Neuromuscular Junction

Structural Organization of the Neuromuscular Junction

Neuromuscular Transmission

Coexistence of Transmitters and Neuromodulators

Adenosine as a Neuromodulator at the Neuromuscular Junction

Pathways: Synthesis and Degradation of Adenosine at the Neuromuscular Junction

Adenosine Receptors

Nerve Terminals

Schwann Cells

Adenosine Receptors and Their Interactions With Other Receptors at the Neuromuscular Junction

Crosstalk Between A1 and A2A Receptors

Crosstalk Between Adenosine Receptors and Acetylcholine Receptors

Adenosine Receptors and BDNF Actions

Adenosine Signaling in Ageing and Disease

Conclusions

References

5 Gene Regulation of Adenosine A2A Receptors in the Central Nervous System

General Introduction

A2AR Promoter and Gene Structure

Epigenetics of ADORA2A

Use of DNA Methylating Agents as a Therapeutic Tool

The Dual Codon Properties of the A2AR Gene

Concluding Remarks

Acknowledgments

References

II. Pathology

6 Sleep, Adenosine, and Neurodegeneration

Sleep Phenomenology and Adenosine

Sleep and Adenosine Changes Across Normal Ageing

Sleep Changes in Alzheimer’s Disease

Mechanisms of Alzheimer’s Disease Influence on Sleep

Changes in ADORA1 and ADORA2 Expression

Association of Alzheimer’s Disease Biomarkers and Sleep

Role of Sleep Loss in Alzheimer’s Disease

Sleep Changes in Parkinson’s Disease

Parkinson’s Disease Role in Sleep Pathology

Role of Sleep Loss in Parkinson’s Disease Pathology

Treatment Related Issues

Summary

References

7 Neuronal vs Glial Cell Contribution to Adenosine A2A Receptor-Induced Neurodegeneration

Neurodegeneration and Neurodegenerative Diseases

Excitotoxicity

Neuroinflammation

Role of A2A Receptors in Neurodegeneration

Adenosine A2A Receptors and Parkinson’s Disease

Adenosine A2A Receptor in Huntington’s disease

Adenosine A2A Receptor in Alzheimer Disease

Adenosine A2A Receptor in Ischemia

Adenosine A2A Receptor in Multiple Sclerosis

Adenosine A2A Receptor in Amyotrophic Lateral Sclerosis

Conclusions

References

8 Adenosine and Oxygen/Glucose Deprivation in the Brain

Introduction

Adenosine is Released by Ischemia and Stimulate All P1 Receptor Subtypes

Role of Adenosine Receptors in Ischemia

Adenosine A1 Receptors are Protective

Adenosine A2A Receptor Antagonists are Protective Against Ischemic Damage

A2A Receptor Antagonists Protect From the Increase of Glutamatergic Excitatory Transmission

A2A Receptor Antagonists Protect from Ischemia-Induced Activation of Intracellular Pathways

Adenosine A2A Receptor Agonists are Protective Against Ischemic Damage

Adenosine A2B Receptors in Brain Ischemia

Adenosine A3 Receptors in Brain Ischemia

Conclusions

Acknowledgments

References

9 Adenosine Receptors and Memory Disorders

Alzheimer’s Disease

Caffeine May Protect Against Cognitive Decline and AD

Caffeine, Adenosine Receptor and AD Lesions

Conclusion

Acknowledgments

References

10 Control of Motor Function by Adenosine A2A Receptors in Parkinson’s and Huntington’s Disease

Introduction

Basal Ganglia Circuitry

Adenosine A2A Receptor Antagonists

Parkinson’s Disease

Effect of A2A Receptor Antagonists on Motor and Sensorimotor Deficits

Parkinsonian Tremor and Involvement of A2A Receptors

Parkinsonian Muscle Rigidity and Involvement of A2A Receptors

A2A Receptor Antagonists on l-Dopa-Induced Motor Complications

Clinical Studies on A2A Receptor Antagonists in Parkinson’s Disease

Modulation of Adenosine A2A Receptors and Interaction With the Other Neurotransmitter Systems

Interaction Between A2A Receptor Antagonists and Dopaminergic Receptors

Interaction Between A2A Receptor Antagonists and Glutamate Receptors

Interaction Between A2A Receptor Antagonists and Cannabinoid Receptors

Interaction Between A2A Receptor Antagonists and 5-HT Receptors

Adenosine A2A Receptors and Huntington’s Disease

Conclusions

References

11 Adenosine Receptors Oligomers in Parkinson’s Disease

Introduction

Adenosine Receptors in the Brain

Adenosine Receptor-Containing Oligomers

Parkinson’s Disease and Adenosine Receptor Oligomers: Impact on Pharmacotherapy

Concluding Remarks

Acknowledgments

References

12 Adenosine Control of Striatal Function—Implications for the Treatment of Apathy in Basal Ganglia Disorders

Introduction

Dopamine Control of Striatal Function

Differential Dopamine Control of the Direct and Indirect Striatal Efferent Pathways, the “Go” and “NoGo” Pathways

Differential Adenosine Control of the “Go” and “NoGo” Pathways. The Adenosine–Dopamine Receptor Heteromers

Adenosine Control of the Striatal Glutamate Terminal. The A1R–A2AR Heteromer

Dopamine and Striatal Dysfunction. Apathy Versus Akinesia

Targeting Adenosine Receptor Heteromers for the Treatment of Apathy

Acknowledgments

References

Index

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