Abstract
Summary
This report describes the role of neuroprotection in acute disorders such as
stroke and injuries of the nervous system as well as in chronic diseases such
as neurodegenerative disorders because many of the underlying mechanisms of
damage to neural tissues are similar in all these conditions and several
products are used in more than one disorder. Over 500 products have been
investigated for neuroprotective effects including those from the categories
of free radical scavengers, anti-excitotoxic agents, apoptosis (programmed
cell death) inhibitors, anti-inflammatory agents, neurotrophic factors, metal
ion chelators, ion channel modulators and gene therapy. Some of the agents are
old established pharmaceuticals whereas others are new biotechnology products.
Pathomechanisms of diseases are described with steps at which neuroprotective
therapies are directed. Diseases covered include cerebrovascular disorders,
traumatic brain injury, spinal cord injury, Alzheimer's disease, Parkinson's
disease, Huntington's disease, amyotrophic lateral sclerosis, multiple
sclerosis, epilepsy and ischemic optic neuropathy as well as retinal
degeneration. Although anesthetics such as propofol are neuroprotective as
well, neuroprotection during surgery and anesthesia is discussed with the aim
of preventing and treating complications that result in CNS damage.
The report contains a profile of 131 companies that have a neuroprotective
product or products along with 112 collaborations. Some of the products in
development at academic institutions that do not have a commercial sponsor are
also included. Although an up-to-date search of the literature was performed
and selected 850 references are included, a considerable amount of information
has not been published anywhere else. Clinical trials of various
neuroprotective agents are described and failures of trials are analyzed with
suggestions for improving the selection of drugs and design of trials.The
report is supplemented with 65 tables and 11 figures.
Market analysis of currently used productsthat have a neuroprotective effect
are analyzed for the year 2011. Some of these products are approved for other
indications but are known to have a neuroprotective effect. With the approval
of new products and takeover of markets for obsolete symptomatic therapies,
the neuroprotection market value will rise by the year 2016 when it will
constitute a major and important component of the CNS market. Forecasts are
made until 2021. By that time neuroprotection will be an established part of
the neurological practice and measures will be available to achieve this
effectively.
Table of Contents
Part I
0. Executive Summary 25
1. Introduction 29
- Definitions 29
- Historical development of neuroprotection 29
- Intrinsic neuroprotective factors 30
- Neuroprotective gene expression 31
- Upregulation of GADD34 31
- Induction of NR4A proteins by CREB in neurons 32
- Neurotrophic factors 32
- Intrinsic nonenzymatic antioxidants 32
- Activation of transcription factor Nrf2 33
- Intrinsic neuroprotective proteins 33
- αB-crystallin 33
- Excitatory amino acid transporters 33
- Extracellular serine protease thrombin 33
- Galanin 34
- Neuroglobin 34
- Nuclear factor I-A 34
- Prion protein 35
- Rai adaptor protein 35
- Stem cell factor 35
- Role of the immune system in neuroprotection 36
- Induction of DNA repair enzymes for neuroprotection 36
- Pathomechanisms of CNS injury as basis for neuroprotection 37
- Biomarkers of neurological disorders and neuroprotection 37
- CNS biomarker identification using proteomics 37
- Brain imaging for detection of biomarkers 38
- Role of neuroprotection in various neurological disorders 38
- Neuroprotection and neuroregeneration 39
- Acute versus chronic neuroprotection 39
- Discovery and evaluation of neuroprotective agents 40
- Neuroprotective drug discovery 40
- Discovery of CNS drugs that penetrate the blood-brain barrier 41
- In vitro assays for the evaluation of neuroprotective agents 41
- Oxidative injury model to test neuroprotective drugs 41
- Apoptosis model for designing neuroprotective drugs 42
- Transgenic mouse models of neurological disorders 42
- Evaluating effects of neuroprotective drugs on living brain slices 42
- Role of brain imaging in neuroprotective drug discovery and development
43
- Positron emission tomography 43
- Role of single photon emission computed tomography 43
- Functional CT scanning to evaluate cerebrovascular protection 44
- Magnetic resonance imaging for the evaluation of neuroprotectives 44
- Application of nanotechnology to neuroprotection 45
- Evaluation criteria for potential neuroprotective agents 45
2. Neuroprotective Agents 47
- Classification of neuroprotective agents 47
- α2 adrenoreceptor agonists 51
- Dexmedetomidine 51
- Activated protein C 51
- Activity-dependent neuroprotective protein 52
- Adenosine analogs 52
- Propentofylline 53
- Antidepressants 53
- Antidepressant-induced neurogenesis 53
- Neurogenesis induced by electroconvulsive therapy 53
- Neuroprotective effect of selective serotonin reuptake inhibitors 54
- Antiepileptic drugs as neuroprotectives 56
- Phenytoin 57
- Valproic acid 57
- Levetiracetam 57
- Antiinflammatory agents 58
- Aspirin 58
- Interleukin-1 antagonists 58
- COX-2 inhibitors 59
- Nimesulide 59
- Gold microparticles as anti-neuroinflammatory agents 59
- Minocycline 59
- Prostaglandin receptor antagonists 60
- Anti-apoptosis agents 61
- Activated protein C 62
- Calpain inhibitors 62
- Caspase inhibitors 62
- DNA binding drugs 62
- Lithium 63
- Olesoxime 63
- Omega-3 fatty acids 63
- Docosahexaenoic acid 64
- Poly(ADP-ribose) polymerase inhibitors 64
- Prevention of apoptosis by binding of proNGF to sortilin 65
- Antioxidants/free radical scavengers 65
- Free radical generation 65
- Natural defenses against oxidative stress 66
- Effects of oxidative damage 66
- Oxidative damage and aging 66
- Neuronal damage by free radicals 67
- Oxidative damage and neurodegenerative disorders 67
- Measures to control oxidative stress 67
- Categories of therapeutic antioxidants 67
- Alpha-phenyl-tert-butylnitrone 68
- Coenzyme Q10 68
- Dihydroergocryptine 69
- Flavonoids 69
- Mitochondria-targeted antioxidants 70
- Nanoparticles as neuroprotective antioxidants 70
- Neuroleptics as antioxidants 71
- Nitrones 71
- Translation of antioxidant neuroprotection from preclinical to clinical
71
- Carbon monoxide and heme oxygenase 72
- Cell transplants 72
- Cells secreting neuroprotective substances 72
- Stem cells 73
- Stem cell activation for neuroprotection/regeneration by glucocorticoids
73
- Cytokines 73
- Erythropoietin 73
- Non-erythropoietic EPO variants and mimics 75
- Granulocyte colony-stimulating factor 75
- Delta-opioid receptor agonists 76
- FK960 76
- Gene therapy 76
- Glucagon-like peptide 77
- Glatiramer acetate 78
- Glutamate antagonists 78
- Neuroprotection by scavenging blood glutamate 79
- N-acylethanolamines for protection against glutamatergic excitotoxicity
79
- Glutamate transporters 79
- Glutamate transporter-mediated neuroprotective effect of drugs 80
- Neuroprotection by targeting KAI subunit of kainate receptor 80
- Glycine-proline-glutamate analogs 81
- Herbal preparations 81
- Flavonoid wogonin 81
- Ginseng 81
- Hydrogen sulfide 82
- NMDA receptor ion channel complex 82
- NMDA receptor antagonists 84
- NMDA NR2B subunit receptor antagonists 84
- Ifenprodil 84
- Memantine as a neuroprotective agent 84
- Magnesium 84
- NAALADase inhibitors 85
- Gacyclidine 85
- N-alkylglycines 85
- AMPA receptor modulators 86
- Metabotropic glutamate receptor modulators 86
- Cannabinoids 87
- Dexanabinol 87
- Glutathione 88
- Heat shock proteins 88
- Hormones 88
- Estrogen and neuroprotection 88
- Neuroprotective effect of estrogen receptor ligands 89
- Selective estrogen receptor modulators 89
- Mitochondrial mechanisms of estrogen neuroprotection 90
- Insulin 90
- Ion Channel modulators 91
- Calcium channel blockers. 91
- Ziconotide 91
- Na+ channel blockers. 92
- Neuroprotective potassium channel inhibitors 92
- Kynurenine inhibitors 93
- Leukocyte adhesion inhibitors 93
- Modafinil 94
- Neural regeneration protein 94
- Neurite outgrowth-promoting prostaglandin compounds 94
- Neuroimmunophilins 95
- Cyclosporin-A 95
- FK506 96
- Rapamycin 96
- Neurotrophic factors 96
- Activity-dependent neurotrophic factor 97
- Bone morphogenetic proteins 97
- Brain-derived neurotrophic factor 97
- Ciliary neurotrophic factor 98
- Fibroblast growth factors 98
- Glial cell line-derived neurotrophic factor 99
- Insulin-like growth factor 99
- Nerve growth factor 100
- Neurotrophins 100
- Osteogenic protein-1 101
- Pigment epithelium-derived factor 101
- Transforming growth factor-β 101
- Vascular endothelial growth factor 101
- Neurotrophic factor-related neuroprotective agents 102
- Amitriptyline as a TrkA and TrkB receptor agonist 102
- Colivelin 102
- Gambogic amide 102
- Inosine 103
- Meteorin 103
- Oxygen-regulated protein 150 kD 103
- Prosaptide 103
- Siagoside 104
- Small molecule activators of the Trk receptors 104
- Nicotine and nicotinic receptor agonists 105
- Neuroprotective effect of galantamine mediated via α7nAChRs 105
- Galantamine-induced Aβ clearance via α7nAChRs 105
- Nitric oxide-based neuroprotection 106
- Nitric oxide synthase inhibitors 106
- Nitric oxide mimetics 107
- Nootropics 107
- Piracetam 108
- Nutraceuticals and food constituents 108
- Coffee 108
- Creatine 108
- Curcumin/curry 109
- Curcumin as a neuroprotectant in Alzheimer disease 109
- Curcumin as a neuroprotectant in stroke 109
- Curcumin as a neuroprotectant in multiple sclerosis 110
- Mechanism of neuroprotective effect of curcumin 110
- Glyceryltriacetate 110
- Green tea 110
- Nicotinamide 111
- Resveratrol 111
- Osmotic diuretics 112
- Mannitol 112
- Osteopontin 112
- Oxygen therapeutics 113
- Oxygen carriers 113 - 8 -
Hemoglobin-based oxygen carriers 113 Perfluorocarbons as oxygen
carriers 114 Hyperbaric oxygen therapy 115 Peptides
115 C3-derived peptide for neuroprotection and neuroregeneration 115
Corticotropin-releasing hormone 115 Thyrotropin-releasing hormone
116 Vasoactive intestinal peptide 116 Pharmacological
preconditioning 116 PPARs as drug targets for neuroprotection
117 Riluzole 117 Role of RNA interference in neuroprotection
118 Sigma receptor agonists as neuroprotective agents 118 SIRT group
of proteins 118 Statins 119 Steroids 120
Dehydroepiandrosterone 120 HF0220 120 Sulforaphane
121 Tauroursodeoxycholic acid 121 Tetanus toxin as a
neuroprotective agent 121 Thrombolytic agents as neuroprotective agents
122 Uncoupling protein 2 122 Vaccines as neuroprotectives
122 Vitamins as neuroprotective agents 123 Vitamin B12
123 Vitamin D 124 Non-pharmacological approaches to
neuroprotection 124 Environmental enrichment 124 Mental
training 124 Physical exercise 124 Hypothermia
125 Limitations of hypothermia 125 Hypothermic neuroprotection in
hypoxia-ischemia 126 Hibernation induced by hydrogen sulfide
126 Ketogenic diet 126 Nonpharmacological preconditioning for
neuroprotection 127 Transcranial magnetic stimulation 128
Electrical fields for improvement of cerebral function in neurodegeneration
128 Neuroprotective effect of exercise 129 Hibernation and
neuroprotection 129 Suspended animation and neuroprotection 130
3. Neuroprotection in Cerebrovascular Disease 132
- Introduction 132
- Pathophysiology of cerebral ischemia 132
- Calcium overload 133
- Ion channel dysfunction in stroke 133
- Role of oxygen free radicals in cerebral ischemia 134
- Role of nitric oxide in cerebral ischemia 134
- Glutamate as a biomarker of stroke 134
- Cerebral edema in stroke 134
- Gene expression in response to cerebral ischemia 135
- Induction of heat shock proteins in stroke 135
- Role of cytokines and adhesion molecules in stroke 135
- Tumor necrosis factor-α 135
- Interleukin-1 and IL-6 136
- Adhesion molecules 136
- DNA damage and repair in cerebral ischemia 136
- Role of neurotrophic factors in stroke 137
- Problems requiring investigation of the role of NTFs in stroke 137
- Role of Poly(ADP-ribose) polymerase (PARP) gene 137
- Role of protease-activated receptor 1 138
- Reperfusion injury after cerebral ischemia 138
- Neuroprotection according to zones in cerebral infarction 138
- Zone of ischemic infarction 138
- Penumbra 139
- Current management of stroke 139
- Neuroprotection in stenosis of intracranial arteries 140
- Neuroprotection in transient ischemic attacks 140
- Neuroprotective therapies for stroke 140 - 9 -
αB-crystallin as a neuroprotectant in stroke 141 Acid-sensing
ion channel blockers 142 AMPA receptor antagonists as neuroprotectives
for stroke 142 Zonampanel 142 Antiapoptotic neuroprotectives
142 NIM811 142 Creatine as neuroprotective in stroke
143 Lithium as a neuroprotective in stroke 143 TUDCA as a
neuroprotective in stroke 143 Coagulation inhibitors as
neuroprotectives 143 Heparin and enoxaparin 144 Warfarin vs
dabigatran 144 Apixaban 144 Antiepileptic drugs as
neuroprotectives in stroke 145 Tiagabine 145 Topiramate
145 Zonisamide 145 Anti-HMGB1 monoclonal antibody 145
Antioxidant approaches 146 Carnosine as a neuroprotective in stroke
146 Dehydroascorbic acid 146 Tocotrienols 147 Uric
acid 148 Antiglutamate compounds 148 MRZ 2/576
148 L-Phenylalanine 148 Arimoclomol for stroke 148
Cardiac glycosides as neuroprotectives in stroke 149 Clenbuterol
149 Cox-2 inhibitors for ischemic stroke 149 Docosahexaenoic acid
for ischemic stroke 149 Estrogen for stroke 150 Extendin-4
151 Flavones for neuroprotection in stroke 151
Granulocyte-macrophage colony-stimulating factor for cerebral ischemia 152
Modulation of histamine H2-receptors 152 Inosine for stroke
152 Insulin-like growth factor-I 153 Intravenous immunoglobulin as
neuroprotective in stroke 153 Ischemic preconditioning for
neuroprotection in stroke 153 Ketone bodies for neuroprotection in
stroke 154 Mineralocorticoid receptor blockade for neuroprotection
154 Multifunctional neuroprotective agents 154 Nasal delivery of
neuroprotective agents in stroke 155 Neuroserpin as a neuroprotective in
stroke 155 N-2-mercaptopropionyl glycine 155 NeuroAid
156 Neurotrophic factors as neuroprotectives for stroke 156 AX200
156 Brain-derived neurotrophic factor 156 Fibroblast growth
factor 157 Glial cell line-derived neurotrophic factor 157
Insulin-like growth factor-1 157 Neuregulin-1 158 NO-based
strategies for neuroprotection in cerebral ischemia 158 Pannexin channel
blockers for neuroprotection in stroke 159 Perlecan domain V
159 Peroxisome proliferator-activated receptor-γagonists 159 PGE2
EP2 receptor activation 159 Pioglitazone for reduction of stroke risk
in diabetes 160 Progesterone 160 Proteosome inhibitors
160 Statins for prevention and neuroprotection in stroke 160
Sildenafil 161 Src receptor blockade 161 Stroke vaccine
162 SUN N4057 162 Thrombosis inhibitors 162
Aspirin 162 Clopidogrel 163 Dipyridamole 163
Vitamin E for neuroprotection in stroke 163 Neuroprotection in
reperfusion injury 164 Prevention of hemorrhage following ischemic
stroke 164 Non-pharmacological neuroprotective therapies for stroke
165 Preconditioning for neuroprotection against cerebral ischemia 165
Hypothermia for neuroprotection in acute stroke 165 Hyperbaric oxygen
therapy for neuroprotection in acute stroke 166 Infrared laser therapy
for ischemic stroke 167 Neurostimulation of sphenopalatine ganglion
167 Neurosurgical procedures for neuroprotection in stroke 167
Neurorehabilitation in relation to neuroprotection in stroke 168 Cell
therapy for stroke 169 Stem cell transplant for stroke 169
Immortalized cell grafts for stroke 169 Stimulation of instrinsic stem
cells for repair of brain in stroke 170 Neuroprotective vaccines for
stroke 170 Gene therapy for neuroprotection in cerebrovascular
disease 170 Regulation of microRNAs for neuroprotection in cerebral
ischemia 172 RNAi-based therapy for neuroprotection in stroke 173
Neuroprotective therapies for cerebral ischemia: clinical trials 173
Albumin 174 Free radical scavengers 174 DP-b99
175 Minocycline for neuroprotection in stroke 176 Perindopril
176 Failed clinical trials of neuroprotection in stroke 176 Ancrod
178 Aptiganel 178 Cerovive 178 Citicoline
179 Desmoteplase 180 Erythropoietin as a neuroprotective in
stroke 181 SPD 502 181 Tirilazad mesylate 182
Selfotel 182 Lubeluzole 182 Nalmefene 183
Gavestinel 183 Nimodipine 183 Sipatrigine 183
Causes of failure of stroke trials 184 Measures for prevention of
failures in stroke trials 185 Design of acute stroke trial to
facilitate drug approval 187 The ideal neuroprotective agent for stroke
187 Future prospects for neuroprotection in stroke 188
4. Neuroprotection in Traumatic Brain Injury 190
- Introduction 190
- Cerebral hypoxia/ischemia as a complication of trauma 190
- Epidemiology of TBI 190
- TBI in the military 191
- Pathophysiology of TBI 191
- Immediate damage following TBI 192
- Cerebral edema following TBI 192
- Delayed damage following TBI 192
- Mechanism of axonal damage after TBI 192
- Role of neuroinflammation in TBI 192
- Molecular events following TBI 193
- BBB damage after TBI 193
- Chronic traumatic encephalopathy 193
- Neurocognitive sequelae of TBI 194
- Changes in neurotrophic factors following TBI 195
- Changes in neurotransmitters following TBI 195
- Proteomics of TBI 195
- Genetic influences on outcome following TBI 196
- Management of TBI 196
- Control of intracranial pressure and cerebral edema 197
- Corticosteroids 197
- Neuroprotection in TBI 198
- Amantadine 199
- Antiepileptic drugs for prevention of seizures and neuroprotection 199
- Antioxidants 199
- Barbiturates 200
- β- and γ-secretase inhibitors 200
- Beta blockers 200
- Bradykinin B2 antagonists 201
- Cell cycle inhibitors for TBI 201
- COX-2 inhibitors for neuroprotection in TBI 201
- Cyclosporin for neuroprotection in TBI 202
- Dexanabinol for TBI 202
- Erythropoietin for neuroprotection in TBI 202
- Gold implants for neuroprotection in focal TBI 202
- KN 38-7271 203
- Levosimendan 203
- Magnesium sulfate 203
- Minocycline for TBI 203
- Nutritional approaches to neuroprotection in TBI 204
- Branched chain amino acids to ameliorate cognitive impairment in TBI
204
- Creatine for neuroprotection in TBI 204
- Nicotinamide for neuroprotection in TBI 205
- Omega 3 fatty acids as neuroprotectives in TBI 205
- Neurotrophic factors for TBI 206
- Neurosteroids as neuroprotective agents for TBI 206
- NMDA receptor antagonists 207
- NP-1 208
- Nogo-A inhibitor 208
- Oxygen carriers for TBI 208
- Polyethylene glycol for neuroprotection in TBI 209
- Propofol for neuroprotection in TBI 209
- Rapamycin as neuroprotective in TBI 209
- Simvastatin as neuroprotective in TBI 210
- Thyrotropin-releasing hormone analogs 210
- Traxoprodil 210
- Biological approaches to neuroprotection in TBI 211
- Antisense approaches to TBI 211
- Cell therapy for TBI 211
- Gene therapy for TBI 211
- Vaccines for TBI 212
- Non-pharmaceutical approaches to neuroprotection in TBI 212
- Hyperbaric oxygen therapy for TBI 212
- Hypothermia 212
- Reduction of microglial migration after TBI 212
- Deep brain stimulation for TBI 213
- Prophylactic neuroprotection against TBI 213
- Role of helmets in protection against TBI 213
- Role of physical exercise in protection against TBI 214
- Clinical trials of neuroprotective agents in TBI 214
- Ongoing clinical trials in TBI 214
- Failed clinical trials in TBI 215
- Differences between clinical trials and studies in animal models of TBI
216
- Subgroup analysis 216
- Improving the clinical trial design 217
- Clinical trials combining multiple treatment strategies 217
- Shortening the trial time 217
- Conclusions and future prospects of neuroprotection in TBI 217
5. Neuroprotection in Spinal Cord Injury 220
- Introduction 220
- Pathophysiology of SCI 220
- Secondary mechanisms of SCI 221
- Neurotrophic factor changes in SCI 222
- Management of SCI 223
- Pharmacological neuroprotective agents for SCI 224
- 4-aminopyridine 224
- Antibodies as neurite growth inhibitors in SCI 224
- Bacterial enzyme chondroitinase ABC 224
- Docosahexaenoic acid as neuroprotective in SCI 225
- Erythropoietin as a neuroprotective in SCI 225
- Free radical scavengers for neuroprotection in SCI 225
- Gacyclidine 226
- GYKI 52466 226
- Immunosuppressants as neuroprotectants in SCI 226
- Interleukin-10 for neuroprotection in SCI 226
- Matrix metalloproteinase inhibitors for SCI 227
- Methylprednisolone 227
- Minocycline as neuroprotective in SCI 227
- Neurotrophic factors for neuroprotection after SCI 228
- Promotion of regeneration of neurons in SCI 228
- Rho pathway and Rho antagonists in SCI 229
- Selenium as a neuroprotective for SCI 229
- Sialidase for enhancing recovery after SCI 229
- Targeting the inflammatory response for neuroprotection in SCI 230
- Uric acid as neuroprotective in SCI 230
- Non-pharmacological approaches to SCI 230
- Hyperbaric oxygen therapy 230
- Hypothermia for SCI 230
- Cell therapy for SCI 231
- Autoimmune T cells against CNS myelin-associated peptide 231
- Fetal neural grafts for SCI 231
- Olfactory-ensheathing cells for SCI 231
- Oligodendrocyte precursor cells for treatment of SCI 232
- Schwann cell transplants for SCI 232
- Transplantation of glial cells for SCI 232
- Stem cells for SCI 232
- Bone marrow stem cells for SCI 232
- Embryonic stem cells for SCI 233
- Transplantation of induced pluripotent stem cells in SCI 233
- Transplantation of MSCs for SCI 234
- Transplantation of NSCs for SCI 234
- Transdifferentiation of stem cells into cholinergic neurons for SCI
235
- Gene therapy for SCI 235
- Combined approaches to spinal cord injury 236
- Discovery of new targets for neuroprotective therapies in SCI 236
- Clinical trials in SCI 237
6. Neuroprotection in Neurodegenerative Disorders 238
- Introduction 238
- Pathomechanism of neurodegeneration 238
- Dual role of α synuclein in neuroprotection and neurodegeneration
238
- Lack of neurotrophic factors 239
- Neuroinflammation in neurodegenerative disorders 239
- Neurodegeneration associated with protein misfolding 239
- Modulation of neurodegeneration by molecular chaperones 239
- Intrabodies targeting protein misfolding in neurodegeneration 240
- Targeting proteins aggregation to prevent amyloid formation 240
- Tau and neurodegeneration 240
- TDP-43 proteinopathy and neurodegenerative diseases 241
- Role of apoptosis in neurodegenerative disorders 241
- Role of glia in neurodegeneration 241
- Role of metals in neurodegeneration 242
- Viral infections and neurodegeneration 242
- AIDS and the nervous system 242
- Avian influenza as cause of neurodegeneration 243
- Genetic disorders with neurodegeneration 244
- Batten disease 244
- Friedrich ataxia 245
- Pathomechanism of FA 245
- Neuroprotection in FA 245
- Niemann-Pick type C disease 245
- Creutzfeldt-Jakob disease 246
- Approaches to neuroprotection in neurodegenerative disorders 247
- Glutamate-based therapies for neurodegenerative disorders 247
- Iron chelation for neuroprotection 248
- Mitochondria permeability transition pore complex and neuroprotection
248
7. Neuroprotection in Parkinson Disease 250
- Introduction 250
- Epidemiology of Parkinson's disease 250
- Pathophysiology of Parkinson's disease 250
- Oxidative stress 251
- Excitotoxicity 252
- Asynchronous neuronal activity 252
- Apoptosis 252
- Role of neurotrophic factors 252
- Role of misfolding proteins 252
- Genetic factors in PD 253
- Alteration of dopamine homeostasis 254
- Neuroprotective strategies for PD based on pathomechanism 254
- RNAi screening to identify neuroprotective genes in a PD model 255
- Management of Parkinson's disease 256
- Limitation of conventionally administered dopamine therapy 257
- Treatment of dementia associated with PD 258
- Neuroprotective therapy in PD 258
- Neuroprotective effect of currently used drugs for PD 258
- Pramipexole 258
- Rasagiline mesylate 259
- Ropinirole 260
- Selegiline 260
- Non-pharmacological strategies for neuroprotection in PD 261
- Effect of exercise and environmental enrichment on PD 261
- Low-calorie diet in PD 261
- Development of neuroprotective therapies for PD 262
- 2B3-201 for targeted delivery of methylprednisolone 262
- 9-methyl-β-carboline 262
- Adenosine AA2 receptor antagonists 262
- Antiapoptotic strategies for PD 263
- Calcium channel blockers for PD 263
- Cell therapies for PD 263
- Stem cells for PD 263
- Activation of endogenous stem cells and neural precursors 264
- Cogane 265
- Creatine and minocycline 265
- Conserved dopamine neurotrophic factor for PD 265
- Free radical scavengers for neuroprotection in Parkinson's disease 266
- Antioxidants 266
- Melatonin 266
- Tea extracts as neuroprotectives 266
- Nicotine as a neuroprotective in PD 267
- Gene therapy for PD 267
- Implantation of genetically engineered cells 267
- Gene therapy using GDNF and neurturin 268
- Glutamic acid decarboxylase gene therapy 268
- Parkin gene therapy 269
- Concluding remarks about gene therapy for PD 269
- Heat shock protein 70 270
- Neuroprotective effect of leucine-rich repeat kinase-2 inhibitors 270
- Neuroprotective effect of DJ-1 protein 270
- Neurotrophic factors 270
- Basic fibroblast growth factor for PD 270
- BDNF for PD 271
- GDNF for PD 271
- MANF for PD 272
- Neurturin for PD 272
- Platelet derived growth factor 272
- Clinical trials with NTFs 272
- Nrf2-mediated neuroprotection in PD 273
- Omega-3 polyunsaturated fatty acids 273
- RAB3B overexpression 273
- RNAi therapy for PD 274
- Safinamide 274
- Sirtuin 2 inhibitors for neuroprotection in PD 274
- Statins and PD 275
- Targeting Bax 275
- Vitamin D for neuroprotection in PD 275
- Vaccine for PD 276
- Clinical trials of neuroprotection in Parkinson's disease 276
- Evaluation of neuroprotective therapies for PD 278
- Current status and future challenges for neuroprotection in PD 279
8. Neuroprotection in Alzheimer Disease 281
- Introduction 281
- Pathomechanism of Alzheimer's disease 281
- Role of glutamate transport dysfunction in AD 282
- Role of neurotrophic factors in the pathomechanism of AD 282
- Management of Alzheimer's disease 282
- Neuroprotection in Alzheimer's disease 283
- Inhibition of Aβ formation and aggregation 284
- AN-1792 284
- Cadmium telluride nanoparticles prevent Aβ fibril formation 285
- Clioquinol 285
- Colostrinin 286
- FKBP52 for neuroprotection from Cu toxicity in AD 286
- Monoclonal antibody m266 286
- Phenserine 286
- Secretase inhibitors 287
- Inhibition of neuroinflammation 287
- Etanercept 287
- Neurotrophic factors/ gene therapy 288
- NGF gene therapy 288
- AL-108 289
- Targeting plasminogen activator inhibitor type-1 gene 289
- Estrogen and AD 290
- Antioxidants 290
- NSAIDS 290
- Memantine 290
- Dimebon 291
- Cerebrolysin 292
- Ginko biloba 292
- Tetrahydrocannabinol for neuroprotection in AD 293
- Ladostigil tartrate 294
- Phosphodiesterase inhibitors as neuroprotectives 294
- PPAR-γ agonists 294
- Role of statins in reducing the risk of AD 294
- Combined therapeutic approaches to AD 295
- Clinical trials in AD 295
- Future prospects of neuroprotection in AD 302
- Mild cognitive impairment 303
- Relation of MCI to AD 303
- Neuroprotection in MCI 304
9. Neuroprotection in Huntington Disease 305
- Introduction 305
- Pathophysiology of HD 305
- Management of Huntington's disease 306
- Neuroprotection in Huntington's disease 307
- Antipsychotic D2 and 5-HT1A antagonists 308
- Caspase inhibitors 308
- Clioquinol for HD 308
- Creatine for stabilizing bioenergetic defects 308
- Cysteamine 309
- Drugs that block inappropriate calcium release from neurons 309
- Enhancing protease activity for clearance of mHtt 309
- Eicosapentaenoic acid 309
- Free radical scavengers 310
- Histone deacetylase inhibitors 310
- Inhibitors of polyglutamine aggregation HD 310
- Pridopidine 311
- Simvastatin as a neuroprotective in HD 311
- Single chain Fv antibodies 312
- SIRT1 activators for neuroprotection in HD 312
- SIRT2 inhibitors for neuroprotection in HD 312
- Synaptic activation of NMDA receptors 313
- Tetrabenazine 313
- Combinatorial therapy and targeting multiple pathways in HD 313
- Cell transplants 314
- Neurotrophic factors and gene therapy 314
- RNAi therapy for Huntington's disease 315
10. Neuroprotection in Amyotrophic Lateral Sclerosis 317
- Introduction 317
- Pathophysiology of ALS 317
- Neuroprotective therapies for ALS 319
- Activated protein C 320
- AEOL 10150 321
- AIMSPRO 321
- Anakinra 321
- Arimoclomol for ALS 322
- Antisense therapy 322
- Creatine for ALS 322
- Ceftriaxone for ALS 322
- Coenzyme Q10 for ALS 323
- COX-2 inhibitors for ALS 323
- Dexpramipexole 323
- Diallyl trisulfide 324
- Erythropoietin for ALS 324
- Gene therapy for ALS 324
- Glatiramer acetate 325
- Insulin-like growth factor 325
- Ketogenic diet for neuroprotection in ALS 326
- Lenalidomide 326
- Lithium for neuroprotection in ALS 327
- Methylcobalamin 327
- Minocycline for ALS 327
- Olesoxime as neuroprotective for ALS 327
- ONO-2506 for ALS 328
- Riluzole 328
- RNAi-based therapy for ALS 328
- Sodium phenylbutyrate 329
- Stem cell therapy 329
- Talampanel 329
- Tamoxifen 329
- Vaccination for ALS caused by SOD1 mutations 330
- Vascular endothelial growth factor for ALS 330
- Vitamin E for ALS 330
- Clinical trials of neuroprotective therapies for ALS 331
- Concluding remarks and future prospects 333
11. Neuroprotection in Miscellaneous Neurological Disorders 335
- Introduction 335
- Age-related dementia 335
- Enhancing endogenous neurotrophic support of the aging brain 335
- Pharmacological approaches for treatment of age-related dementia 336
- Physical exercise to prevent decline of mental function with aging 337
- Vascular dementia 337
- Prediction of dementia in persons with vascular risk factors 337
- Management of subcortical vascular dementia 338
- Dementia with Lewy bodies 339
- Neuroprotection in AIDS dementia 339
- Multiple system atrophy 340
- Epilepsy 340
- Mechanisms of neuronal damage in epilepsy 340
- Strategies for neuroprotection in epilepsy 341
- Control of seizures by AEDs and neuroprotection 342
- Prevention of seizures by ketogenic diet 343
- Cell therapy for neuroprotection in epilepsy 344
- Cell therapy of posttraumatic epilepsy 344
- Cell therapy for temporal lobe epilepsy 344
- Cell therapy for pharmacoresistant epilepsies 345
- Gene therapy for neuroprotection in epilepsy 345
- Spinal and bulbar muscular atrophy 346
- Spinal muscular atrophy 346
- Multiple sclerosis 347
- Introduction 347
- Epidemiology of multiple sclerosis 347
- Pathophysiology 348
- Current management of multiple sclerosis 348
- Specific therapies for MS based on pathomechanism 349
- Neuroprotection in multiple sclerosis 349
- Clinical trials of neuroprotective therapies for MS 350
- Neuroprotection by control of progressive forms of multiple sclerosis
353
- Neuroprotection by controlling autoimmune inflammation in the brain
353
- Remyelination for neuroprotection in multiple sclerosis 354
- Agents for neuroprotection in multiple sclerosis 354
- Angiotensin-II inhibitors 354
- Antiglutamate agents 354
- Antioxidants for neuroprotection in MS 354
- Antisense and RNAi approaches to MS 355
- Cell therapy for multiple sclerosis 355
- Cladribine 357
- Dalfampridine in MS 358
- Dimethyl fumarate 358
- DNA vaccine for MS 358
- Erythropoietin as a neuroprotective in MS 359
- Fingolimod (FTY720) 359
- Fusokine composed of GM-CSF and IL-15 for immune suppression 360
- Gene therapy for MS 360
- Ibudilast for MS 360
- IVIG for MS 361
- Kinase inhibitors 361
- Laquinimod 361
- Monoclonal antibodies for MS 361
- Natalizumab 362
- Natural human antibodies for repair of myelin 362
- Neurotrophic factors for multiple sclerosis 363
- Oral immunomodulatory agents for MS 364
- Recombinant T-cell ligands 364
- Statins for MS 364
- Teriflunomide 365
- Concluding remarks on neuroprotection in MS 365
- Neuroprotection in transverse myelitis 365
- Neuroprotection in decompression sickness 366
- Neuroprotection in CSF circulatory disorders 367
- Neuroprotection in hydrocephalus 367
- Neuroprotection in normal pressure hydrocephalus 367
- Neuroprotection in infections of the CNS 368
- Neuroprotection in bacterial meningitis 368
- Mechanism of neural injury in bacterial meningitis 368
- Strategies for neuroprotection 369
- Neuroprotection in cryptococcal meningitis 369
- Neuroprotective approach to rabies 369
- Neuroprotection in cerebral malaria 370
- Neuroprotection in hypertensive encephalopathy 370
- Neuroprotection in toxic encephalopathies 371
- Hepatic encephalopathy 371
- Management of hepatic encephalopathy 371
- Encephalopathy due to organophosphorus poisoning 372
- Neuroprotection against chemotherapy-induced brain damage 372
- Neuroprotection against alcohol 373
- Alcoholic neurologic disorders 373
- Fetal alcohol syndrome 373
- Pathogenesis of alcohol-induced damage to the nervous system 373
- Neuroprotection against neurotoxicity of alcohol 374
- Neuroprotection against radiation encephalopathy 374
- Neuroprotection in hypoxia-ischemia 375
- Neuroprotection in neonatal hypoxic-ischemic brain injury 375
- Minocycline for neonatal hypoxia-ischemia 376
- Nicotinamide mononucleotide adenylyl transferase 1 376
- Nitric oxide inhalation for neonatal hypoxia-ischemia 376
- Plasminogen activator inhibitor-1 for neonatal hypoxia-ischemia 377
- Recombinant erythropoietin for neonatal hypoxia-ischemia 377
- Neuroprotection in carbon monoxide poisoning 377
- Pathomechanism of CO poisoning as a basis for neuroprotection 377
- Management of CO poisoning 378
- Syndrome of delayed post-hypoxic leukoencephalopathy 379
- Neuroprotection of the fetus 379
- Neuroprotection in sleep apnea 379
- Neuroprotection in hypoglycemic coma 380
- Neuroprotection in mitochondrial dysfunction 381
- Mitochondrial permeability transition 381
- Mitochondrial approaches for neuroprotection 382
- Methylene blue 382
- Role of nanolasers in evaluation of mitochondrial neuroprotectants 383
- Neuroprotection in mitochondrial encephalopathies 383
- Neuroprotection in psychiatric disorders 384
- Cognitive impairment in schizophrenia 384
- Neuroprotection in schizophrenia 384
- Electroconvulsive therapy and neuroprotection 385
- Neuroprotection in hearing loss 385
- Causes of hearing loss 385
- Pathomechanism of hearing loss 386
- Prevention and treatment of hearing loss 386
- Hyperbaric oxygen for hearing loss 387
- Stem cell therapy for hearing loss 387
- Auditory hair cell replacement by gene therapy 387
- Pharmaceutical approaches to hearing loss 388
- Neuroprotection of peripheral nerves 389
- Neuroprotective agents for peripheral nerves 389
- Acetyl-L-carnitine for peripheral nerve injuries 389
- Atorvastatin for peripheral nerve injuries 389
- Erythropoietin for neuroprotection in peripheral nerve injuries 390
- Neuroprotection in peripheral nerve injuries 390
- Role of hyperbaric oxygen in peripheral nerve injuries 390
- Role of neurotrophic factors in peripheral nerve injuries 391
- Pharmacological approaches to Schwann cells 391
- Role of gene therapy in neuroprotection of injured peripheral nerves
391
- Schwann cell transplantation for peripheral nerve injury 391
- Peripheral neuropathy 392
- Neuroprotection in diabetic neuropathy 392
- Cell therapy for neuroprotection in diabetic neuropathy 392
- Gene therapy with zinc finger DNA-binding proteins 393
- Neuroprotection in chemotherapy-induced neuropathy 393
- Chronic inflammatory demyelinating polyradiculoneuropathy 393
- Neuroprotection in CIDP 394
12. Neuroprotection of the Optic nerve and the Retina 395
- Introduction 395
- Neuroprotection in optic neuropathy 395
- Neuroprotection in optic neuritis 396
- Neuroprotection in optic nerve trauma 396
- Potential regeneration of the optic nerve 397
- Subthreshold transpupillary thermotherapy for protection of RGCs 397
- Neuroprotection of optic nerve in glaucoma 397
- Aminoguanidine as a neuroprotective in glaucoma 399
- Antiglutamate agents for neuroprotection of optic nerve 399
- Betaxolol 399
- NGF eye drops 399
- Targeting Aβ in glaucoma treatment 400
- TNF-α blockers for neuroprotection in glaucoma 400
- Concluding remarks about neuroprotection in glaucoma 400
- Neuroprotection in retinal ischemia 400
- Endogenous neuroprotection in the retina 401
- β-adrenoceptor antagonists 401
- Brimonidine as a neuroprotective is ischemic retinopathy 402
- Thioredoxin as a neuroprotective agent in retinal ischemia 402
- Erythropoietin for neuroprotection of retinal ischemia 402
- Gene therapy for retinal neuroprotection 403
- Hyperbaric oxygen for central retinal artery occlusion 403
- Protection against oxygen-induced retinopathy 403
- Neuroprotection in macular degeneration 403
- Epidemiology 403
- Pathomechanism of AMD 404
- Current treatment of AMD 404
- Novel neuroprotective strategies against retinal degeneration 405
- Antiangiogenic agents 406
- Protection of retinal cells from oxidative-stress-induced apoptosis
407
- N-acetylserotonin derivatives 407
- Nutritional protection against AMD 407
- Progestogenic hormones 407
- Cell therapy for macular degeneration 408
- Retinal pigment epithelial cells 408
- Encapsulated cells delivering CNTF for geographical retinal atrophy
408
- Stem cells 408
- Neural progenitor cells 409
- Gene therapy for retinal degeneration 409
- RNAi-based treatments for AMD 409
- Neuroprotection in proliferative diabetic retinopathy 410
- Strategies for neuroprotection in diabetic retinopathy 410
- RNAi-based approaches to diabetic retinopathy 411
- Clinical trials for optic nerve and retinal neuroprotection 411
13. Neuroprotection during Anesthesia and Surgery 413
- Introduction 413
- Anesthetic agents as neuroprotectives 413
- Barbiturates 413
- Thiopental 414
- Etomidate 415
- Propofol 415
- Ketamine 415
- Gaseous anesthetics 416
- Isoflurane 416
- Xenon 416
- Local anesthetics 417
- Monitoring of CNS function during anesthesia and surgery 417
- Monitoring of cerebral function 417
- Monitoring of spinal cord function during spinal surgery 417
- Neuroprotection during cardiovascular procedures 418
- CNS complications of cardiac surgery 418
- Neuroprotective strategies during cardiac surgery 419
- Neuroprotection during coronary artery bypass grafting 421
- Neuroprotection before anticipated or induced cardiac arrest 421
- Surgery on the aorta 422
- Spinal cord protection during cardiovascular surgery 422
- Cerebral protection during organ transplantation surgery 422
- Cerebral protection during neurosurgery 423
- Cerebral angiography and endovascular surgery 423
- Cerebral protection during surgery for arteriovenous malformations 423
- Cerebral protection during surgery of intracranial aneurysms 423
- Management of subarachnoid hemorrhage 424
- Vasospasm associated with subarachnoid hemorrhage 424
- Cerebral protection during carotid endarterectomy 426
- Cerebral protection during surgery of brain tumors 426
- Neuroprotective measures prior to surgery 427
- Neuroprotection following surgery 427
14. Commercial Aspects of Neuroprotective Therapies 429
- Introduction 429
- The financial burden of CNS damage 429
- Markets for neuroprotective therapies 429
- Markets according to therapeutic areas 429
- Values of neuroprotective therapies in major world markets 431
- Unmet needs in neuroprotectives 432
- Future prospects of neuroprotective therapies 433
- Challenges in neuroprotective drug development 433
- Promising areas of research in neuroprotection 433
- Autoreactive antibodies 434
- Biological therapies for neuroprotection 434
- Multidisciplinary approaches to neuroprotection 434
15. References 435
Tables
- Table 1-1: Historical landmarks in the development of neuroprotection
29
- Table 1-2: Intrinsic neuroprotective factors 30
- Table 1-3: Common features of pathophysiology of brain damage in diseases
37
- Table 1-4: Place of neuroprotection in management of CNS disorders 38
- Table 1-5: Indications for the use of neuroprotection 39
- Table 2-1: A classification of neuroprotective agents 47
- Table 2-2: The neuroprotective effect of antiepileptic drugs 56
- Table 2-3: Neuroprotective affect of minocycline in animal models 60
- Table 2-4: Classification of antioxidants or free radical scavengers with
neuroprotective potential 68
- Table 2-5: Role of erythropoietin in the nervous system 73
- Table 2-6: Ionotropic glutamate receptors 78
- Table 2-7: Classification of metabotropic glutamate receptors (mGluRs)
78
- Table 2-8: Methods for neuroprotection based on nonpharmacological
preconditioning 127
- Table 3-1: Cerebrovascular diseases that are relevant to neuroprotection
132
- Table 3-2: Neuroprotective strategies for stroke 140
- Table 3-3: Neuroprotective gene transfer in models of cerebral ischemia
171
- Table 3-4: Neuroprotective gene therapy in animal stroke models 171
- Table 3-5: Neuroprotective agents in clinical development for acute
cerebrovascular disease 173
- Table 3-6: Some failed trials for neuroprotective therapy for stroke
176
- Table 3-7: Preclinical assessment of neuroprotective agents in acute
stroke models 185
- Table 4-1: Current conventional management of traumatic brain injury
196
- Table 4-2: Neuroprotective strategies for traumatic brain injury 198
- Table 4-3: Ongoing or completed clinical trials for neuroprotection in TBI
214
- Table 4-4: Discontinued or failed clinical trials for neuroprotection in
TBI 215
- Table 5-1: Secondary mechanisms in spinal cord injury 222
- Table 5-2: Neuroprotective and regenerative approaches for SCI 223
- Table 5-3: Clinical trials for neuroprotection in SCI 237
- Table 6-1: Glutamate-based therapies in clinical development for
neurodegenerative disorders 247
- Table 7-1: Prevalence of Parkinson's disease in major markets 2011-2021
250
- Table 7-2: Factors in the etiology of Parkinson's disease 250
- Table 7-3: Strategies for the treatment of Parkinson's disease 256
- Table 7-4: Current clinical trials of neuroprotective therapies for
Parkinson disease 277
- Table 7-5: Failed clinical trials of neuroprotective therapies for
Parkinson disease 277
- Table 7-6: Evaluation of neuroprotective agents for PD 278
- Table 8-1: Cholinergic approaches to the treatment of Alzheimer's disease
283
- Table 8-2: Neuroprotective agents for Alzheimer's disease 283
- Table 8-3: Clinical trials for neuroprotection in Alzheimer disease
295
- Table 8-4: Discontinued, failed or inconclusive clinical trials of
Alzheimer disease 300
- Table 8-5: Strategies for discovery of neuroprotective therapies for AD
302
- Table 9-1: Neuroprotective approaches in HD 307
- Table 10-1: Classification of neuroprotective agents for amyotrophic
lateral sclerosis 320
- Table 10-2: Clinical trials of neuroprotective therapies for ALS 331
- Table 10-3: Failed or discontinued trials of neuroprotective therapies for
ALS 332
- Table 11-1: Therapeutic approaches to subcortical vascular dementia
338
- Table 11-2: Pharmacological neuroprotection against the sequelae of
seizures 342
- Table 11-3: Neuroprotective effect of AEDs in animal models of status
epilepticus (SE) 343
- Table 11-4: Specific therapies for MS based on postulated pathomechanisms
349
- Table 11-5: Approved neuroprotective therapies for multiple sclerosis
350
- Table 11-6: Neuroprotective therapies for multiple sclerosis in clinical
trials 351
- Table 11-7: Failed or discontinued trials of neuroprotective therapies for
ALS 351
- Table 11-8: Approaches to neuroprotection in neonatal hypoxia-ischemia
375
- Table 11-9: Drugs with neuroprotective effect at mitochondrial level
382
- Table 11-10: Causes of sensorineural hearing impairment 385
- Table 11-11: Strategies for prevention and treatment of sensorineural
hearing loss 386
- Table 11-12: Agents for neuroprotection of the peripheral nervous system
389
- Table 12-1: Causes of optic neuropathy 395
- Table 12-2: Neuroprotection of the optic nerve in glaucoma 398
- Table 12-3: Strategies for neuroprotection in retinal ischemia 401
- Table 12-4: Novel neuroprotective strategies against retinal degeneration
405
- Table 12-5: Clinical trials for optic nerve and retinal neuroprotection
412
- Table 13-1: CNS complications associated with cardiac procedures 418
- Table 13-2: Strategies for protection of the brain during cardiac surgery
420
- Table 13-3: Medical and surgical methods of cerebral vasospasm management
425
- Table 13-4: Neuroprotection by prevention of vasospasm 425
- Table 14-1: Neuroprotective market values 2011-2021 430
- Table 14-2: Values of neuroprotective therapies in major world markets
from 2011-21 431
Figures
- Figure 2-1: Mechanism of neuroprotective effect of sigma-1 receptor
agonists 55
- Figure 2-2: NMDA receptor ion channel complex 83
- Figure 2-3: Neuroprotective effect of galantamine 105
- Figure 3-1: Some steps in the ischemic cascade and site of action of
neuroprotectives 133
- Figure 3-2: A roadmap for neuroprotection 186
- Figure 4-1: Cascade of events following traumatic brain injury 191
- Figure 5-1: Pathomechanism of acute spinal cord injury 221
- Figure 7-1: Neuroprotective strategies against death of
dopamine-containing neurons in PD 255
- Figure 11-1: Common mechanisms of neural damage in cerebral ischemia and
seizures 341
- Figure 11-2: Role of neuroprotection in epilepsy and its treatment 342
- Figure 8-1: Unmet therapeutic needs in neuroprotective therapies 432
Part II
16. Companies Developing Neuroprotective Therapies 5
- Introduction 5
- Profiles of companies 5
- Collaborations 152
Tables
- Table 16-1: Neuroprotectives in development by AstraZeneca 22
- Table 16-2: Collaborations of companies in the area of neuroprotection
152
