Therapeutic Intranasal Delivery for Stroke and Neurological Disorders (Springer Series in Translational Stroke Research)

The blood-brain-barrier serves to encapsulate and protect the central nervous system, but it also presents a major barricade to therapeutic drug delivery. Poor penetration is the most common hurdle to translating a promising experimental therapy that uses invasive delivery methods to a clinically useful application. In the last 10 years, intranasal delivery of various therapeutic compounds including small chemicals, large proteins, and even stem cells has proven to be very effective in bypassing the blood-brain-barrier and has led to some important advances in translational research for stroke and other neurological diseases. The proposed book will bring together reports from various labs around the world who have had successes in pre-clinical studies of intranasal therapies for various diseases including adult and perinatal stroke, Alzheimer's, Parkinson's, and others.​ Contents 5 Chapter 1: Transnasal Induction of Therapeutic Hypothermia for Neuroprotection 7 1.1 Rhinochill 9 1.2 Transnasal Evaporative Cooling Using Dry Air: (CoolStat Device) 10 References 12 Chapter 2: Hypoxia-Primed Stem Cell Transplantation in Stroke 14 2.1 Stem Cells for Intranasal Cell Therapy 17 2.2 Conditioning Medicine and Cell Survival Mechanisms 18 2.3 Mitochondrial Mechanisms in Stem Cell and Stroke Treatment 19 2.4 Post-ischemic Flow Recovery 20 2.5 Stem Cells and Neuroplasticity 28 2.6 Inflammation, Immune Responses, and Regeneration 29 References 30 Chapter 3: Therapeutic Potential of Intranasal Drug Delivery in Preclinical Studies of Ischemic Stroke and Intracerebral Hemorrhage 32 3.1 Introduction 32 3.2 Mechanisms of Neurologic Damage after Stroke 33 3.3 Intranasal Drug Delivery 34 3.4 IN Treatment for Ischemic Stroke 36 3.4.1 Insulin-Like Growth Factor-1 (IGF-1) 36 3.4.2 Erythropoietin 37 3.4.3 Osteopontin 38 3.4.4 Transforming Growth Factor (TGF) 38 3.4.5 Mesenchymal Stem Cells (MSCs) 39 3.4.6 Other Factors and Reagents 39 3.5 IN Treatment for Intracerebral Hemorrhagic Stroke 40 3.6 Clinical Trials of IN Drug Delivery for Stroke 40 3.7 Future Directions and Conclusion 41 References 42 Chapter 4: Intranasal Drug Delivery After Intracerebral Hemorrhage 48 4.1 Pathophysiology 49 4.1.1 Excitotoxicity 50 4.1.2 Thrombin 50 4.1.3 Hemoglobin and Iron 50 4.2 Neuroprotective Considerations 51 4.3 Emergency Drug Administration 51 4.4 Intranasal Therapeutics in Animal ICH Models 52 4.4.1 Recombinant Proteins 53 4.4.2 Small Molecules 53 4.4.3 Stem Cells 54 4.5 Pitfalls of Systemic Therapy: The Case of Deferoxamine 55 4.6 Conclusions 56 References 57 Chapter 5: Intranasal Treatment in Subarachnoid Hemorrhage 61 5.1 Recombinant Osteopontin in Subarachnoid Hemorrhage 63 5.2 Intranasal Administration of Recombinant Netrin-1 64 5.3 Intranasal Stem Cell Treatment in aSAH 64 5.4 Promising Progress in Intranasal Treatment Research in aSAH 64 5.4.1 Nimodipine-Loaded Lipopluronics Micelles 64 5.4.2 Erythropoietin (EPO) for SAH 65 5.4.3 Insulin and Insulin Liked Growth Factor-1 (IGF-1) 66 References 66 Chapter 6: Intranasal Delivery of Therapeutic Peptides for Treatment of Ischemic Brain Injury 69 6.1 Introduction 69 6.2 Definition and Mechanisms of Intranasal Delivery of Therapeutic Peptides 70 6.3 Advantages of Intranasal Delivery of Therapeutic Peptides 71 6.4 Peptides that Have Been Administered Intranasally to Treat Stroke 72 6.5 Administration Regimens of Intranasal Delivery in the Treatment of Stroke 72 6.6 Disadvantages and Limitations of Intranasal Delivery of Therapeutic Drugs 73 6.7 Future Directions and Concluding Remarks 75 References 75 Chapter 7: Intranasal Delivering Method in the Treatment of Ischemic Stroke 78 7.1 Pathways for Intranasal Administration 79 7.1.1 Transport Across the Olfactory or Respiratory Epithelial Barriers 79 7.1.2 Transport from the Nasal Lamina Propria to Sites of Brain Entry 80 7.1.3 Transport from the Brain Entry Sites to Widespread Sites Within the CNS 80 7.2 Multiple Substances for Intranasal Administration for Ischemic Stroke 81 7.2.1 Proteins and Peptides 81 7.2.2 Stem Cells 83 7.2.3 Gene Vectors 84 7.2.4 Small Molecules and Others 84 7.3 Merits and Issues of Intranasal Administration in Stroke 85 7.3.1 Merits 85 7.3.2 Potential Issues 86 7.3.2.1 Factors Affecting Delivery 86 7.3.2.2 Anatomy Difference Between Rodents and Human 87 7.3.2.3 Local Side Effect 87 7.3.3 Future Direction 88 7.4 Conclusion 88 References 88 Chapter 8: Intranasal Delivery of Drugs for Ischemic Stroke Treatment: Targeting IL-17A 93 8.1 Introduction 94 8.2 Intranasal Delivery for the Treatment of Neurologic Disorders 94 8.3 Intranasal Administration of Growth Factor Confers Protective Effects Against Ischemic Stroke 95 8.4 Intranasal Delivery of IL-17A Promotes Neurogenesis and Functional Recovery After Ischemic Stroke 96 8.5 The Dual Effects of IL-17A in Different Stages of Ischemic Stroke 97 8.6 Intranasal Application of IL-17A After Cerebral Ischemia 98 8.7 Intranasal Application of EPO After Cerebral Ischemia 98 8.8 Conclusion 99 References 99 Chapter 9: Intranasal tPA Application for Axonal Remodeling in Rodent Stroke and Traumatic Brain Injury Models 102 9.1 Different Roles of tPA in the Circulation and CNS Parenchymal Tissue 103 9.2 Intranasal Delivery of tPA into the Brain 104 9.3 Intranasal tPA Administration Improves Neurological Recovery in Stroke and TBI Models 106 9.3.1 Intranasal Administration of tPA 106 9.4 Intranasal tPA Administration Promotes Axonal Remodeling of the Corticospinal Tract (CST) in Stroke and TBI Models 107 9.5 Mechanisms that Underlie tPA Treatment-Induced Axonal Remodeling 109 9.6 Summary 110 References 111 Chapter 10: Therapeutic Intranasal Delivery for Alzheimer’s Disease 117 10.1 Introduction 118 10.2 IN Delivery 118 10.2.1 Advantages and Challenges 118 10.2.2 Pathways of Transport from Nose to Brain 119 10.3 IN Delivery Strategies for AD 121 10.3.1 Tacrine 121 10.3.2 Galantamine 122 10.3.3 Rivastigmine 122 10.3.4 Physostigmine 123 10.3.5 Huperizin A 123 10.3.6 Tarenflurbil 123 10.3.7 Quercetin 124 10.3.8 Insulin 124 10.3.9 Deferoxamine 125 10.3.10 R-Flurbiprofen 125 10.3.11 Curcumin 125 10.3.12 Piperine 126 10.3.13 Angiotensin Receptor Blocker 126 10.3.14 Neurotrophic Factors 126 10.3.15 Peptide 128 10.3.16 Hormone 128 10.3.17 Immunization 129 10.3.18 Cell-Based Therapy 129 10.4 Conclusion and Future Perspectives 130 References 130 Chapter 11: Intranasal Medication Delivery in Children for Brain Disorders 134 11.1 Introduction 135 11.2 History and Development 135 11.3 Characteristics of Intranasal Delivery 136 11.3.1 The Nose: Anatomy and Function 136 11.3.1.1 Nasal Mucosa 136 11.3.1.2 Nasal Mucosal Cilia 136 11.3.2 The Connection Between the Nasal Cavity and the Central Nervous System (CNS) 137 11.3.3 Characteristics of Nasal Administration 137 11.3.3.1 Bioavailability 137 11.3.3.2 Convenience, Compliance, and Costs 138 11.3.3.3 Kinetics 138 11.4 Adverse Effects 138 11.5 Common Uses for Intranasal Medications in Children 139 11.5.1 Sedatives and Analgesia 139 11.5.2 Seizure Control 141 11.5.3 Opioid Antagonists 141 11.5.4 Anti-Migraine 142 11.6 Conclusions 142 References 143 Index 147 Front Matter ....Pages i-vi Transnasal Induction of Therapeutic Hypothermia for Neuroprotection (Raghuram Chava, Harikrishna Tandri)....Pages 1-7 Hypoxia-Primed Stem Cell Transplantation in Stroke (Zheng Zachory Wei, James Ya Zhang, Ling Wei)....Pages 9-26 Therapeutic Potential of Intranasal Drug Delivery in Preclinical Studies of Ischemic Stroke and Intracerebral Hemorrhage (Qian Li, Claire F. Levine, Jian Wang)....Pages 27-42 Intranasal Drug Delivery After Intracerebral Hemorrhage (Jing Chen-Roetling, Raymond F. Regan)....Pages 43-55 Intranasal Treatment in Subarachnoid Hemorrhage (Basak Caner)....Pages 57-64 Intranasal Delivery of Therapeutic Peptides for Treatment of Ischemic Brain Injury (Tingting Huang, Amanda Smith, Jun Chen, Peiying Li)....Pages 65-73 Intranasal Delivering Method in the Treatment of Ischemic Stroke (Chunhua Chen, Mengqin Zhang, Yejun Wu, Changman Zhou, Renyu Liu)....Pages 75-89 Intranasal Delivery of Drugs for Ischemic Stroke Treatment: Targeting IL-17A (Yun Lin, Jiancheng Zhang, Jian Wang)....Pages 91-99 Intranasal tPA Application for Axonal Remodeling in Rodent Stroke and Traumatic Brain Injury Models (Zhongwu Liu, Ye Xiong, Michael Chopp)....Pages 101-115 Therapeutic Intranasal Delivery for Alzheimer’s Disease (Xinxin Wang, Fangxia Guan)....Pages 117-133 Intranasal Medication Delivery in Children for Brain Disorders (Gang Zhang, Myles R. McCrary, Ling Wei)....Pages 135-147 Back Matter ....Pages 149-153 The blood-brain-barrier prevented harmful materials entering the brain and in the meantime is a barricade to therapeutic drug delivery. Intranasal drug delivery to circumvent blood-brain-barrier was developed in the past, to take advantages of a secret passage from the olfactory epithelium into the brain--bypassing the tight junctions that encapsulated the brain from blood circulation. This timely publication of Therapeutic Intranasal Delivery for Stroke and Neurological Disorders presented some of the latest advances in intranasal delivery research, including transnasal hypothermia induction, stem cell intranasal transplantation, intranasal drug delivery in ischemic and hemorrhagic models, intranasal peptides delivery, intranasal tPA application in adults and children. Editors Jun Chen, Jian Wang, Ling Wei and John Zhang are professors from University of Pittsburgh, Johns Hopkins University, Emory University and Loma Linda University in USA