Neuroprotection - Drugs, Markets and Companies |
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0. Executive Summary ..........17 1. Introduction .....................21 Definitions ......21 Historical development of neuroprotection ...21 Intrinsic neuroprotective factors ..................22 Neuroprotective gene expression ..................23 Neurotrophic factors .............23 Intrinsic non-enzymatic antioxidants .............24 Intrinsic neuroprotective proteins..................24 Excitatory amino acid transporters (EAATs) ......................24 Extracellular serine protease thrombin ......24 Neuroglobin....................25 Galanin ...25 Prion protein...................26 Rai (Shc C) adaptor protein .....................26 Stem cell factor ...................26 Role of the immune system in neuroprotection ......................26 Pathomechanisms of CNS injury as basis for neuroprotection ................... 27 Role of neuroprotection in various neurological disorders ...28 Neuroprotection and neuroregeneration.......29 Acute versus chronic neuroprotection...........29 Discovery and evaluation of neuroprotective agents............29 Neuroprotective drug discovery.....................29 Discovery of CNS drugs that penetrate the blood-brain barrier.30 In vitro assays for the evaluation of neuroprotective agents ....30 Oxidative injury model to test neuroprotective drugs ..............31 Apoptosis model for designing neuroprotective drugs..............31 Transgenic mouse models of neurological disorders................32 Brain-on-a-Chip™ technology 32 Role of brain imaging in neuroprotective drug discovery and development .......32 Role of single photon emission computed tomography .......32 Functional CT scanning to evaluate cerebrovascular protection ..................32 Magnetic resonance imaging for the evaluation of neuroprotectives ............33 Application of nanotechnology to neuroprotection...................33 Evaluation criteria for potential neuroprotective agents...........34 Evaluation of neuroprotective effect of drugs approved for other indications ....34 2. Neuroprotective Agents....35 Classification of neuroprotective agents .......35 Activated protein C ................39 Activity-dependent neuroprotective protein .40 Adenosine analogs.................40 Propentofylline....................40 Andepressants 41 Antiepileptic drugs as neuroprotectives........41 Phenytoin....42 Valproic acid.42 Levetiracetam......................42 Antiinflammatory agents........43 Aspirin........43 Interleukin-1 antagonists ......43 COX-2 inhibitors ..................43 Nimesulide .....................44 NS-398...44 Minocycline ..44 VP015.........46 Anti-apoptosis agents ............46 Activated protein C...............46 Calpain inhibitors .................47 Caspase inhibitors ................47 Clusterin ......47 DNA binding drugs ...............48 Lithium ........48 Omega-3 fatty acids .............48 Docosahexaenoic acid ......48 Poly (ADP-ribose) polymerase (PARP) inhibitors .....................49 - 4 - Prevention of apoptosis by binding of proNGF to Sortilin .........50 TRO19622....50 Antioxidants/free radical scavengers ...........51 Free radical generation .........51 Natural defenses against oxidative stress .......51 Effects of oxidative damage...51 Oxidative damage and aging ...................51 Neuronal damage by free radicals ............52 Oxidative damage and neurodegenerative disorders ..........52 Measures to control oxidative stress ..............52 Categories of therapeutic antioxidants ......53 Alpha-phenyl-tert-butylnitrone.................53 Coenzyme Q10 ...............54 Dihydroergocryptine ........54 Flavonoids......................55 Mitochondria-targeted antioxidants...........55 Nanoparticles as neuroprotective antioxidants ..................55 Neuroleptics as antioxidants ....................56 Nitrones..56 Carbon monoxide and heme oxygenase ........57 Cell transplants secreting neuroprotective substances ........57 Cytokines ........58 Erythropoietin.....................58 Granulocyte colony-stimulating factor ............59 Delta-opioid receptor agonists......................60 FK960 .............60 GABA agonists.60 Gene therapy ..61 Glucagon-like peptide ............62 Glatiramer acetate .................62 Glutamate antagonists...........62 Neuroprotection by scavenging blood glutamate ....................63 N-acylethanolamines for protection against glutamatergic excitotoxicity...........64 Glutamate transporters.........64 Glutamate transporter-mediated neuroprotective effect of drugs.....................64 Glycine-proline-glutamate analogs ...............65 Herbal preparations ...............65 Flavonoid wogonin................66 Ginseng .......66 NMDA receptor ion channel complex.............66 NMDA receptor antagonists ...68 NPS 150668 NMDA NR2B subunit receptor antagonists .68 Ifenprodil 68 Memantine .....................68 Magnesium.....................69 NAALADase inhibitors ......69 3,3-bis (3-fluorophenyl) propylamine........69 Gacyclidine (GK-11) ........69 N-alkylglycines................70 Partial NMDA agonists at glycine site .............70 AMPA receptor modulators ....70 Metabotropic glutamate receptor modulators ..71 Cannabinoids71 Dexanabinol (HU-211) ..........72 Glutathione .....72 Heat shock proteins ...............73 Hormones .......73 Estrogen and neuroprotection73 Neuroprotective effect of estrogen receptor ligands ...........74 Selective estrogen receptor modulators ....74 Receptor-independent neuroprotective effects of estrogens 75 Insulin .........75 Ion Channel modulators.........75 Calcium channel blockers. .....76 Ziconotide ......................76 Na+ channel blockers. ...........76 Neuroprotective potassium channel inhibitors .76 Kynurenine inhibitors.............77 Leukocyte adhesion inhibitors77 Modafinil .........78 - 5 - Neural regeneration protein...78 Neurite outgrowth-promoting prostaglandin compounds.....79 Neuroimmunophilins..............79 Cyclosporin ..79 FK506.........80 GPI 1485 .....80 Rapamycin ...80 Neuropeptides81 Corticotropin-releasing hormone ...................81 Neuroprotective peptide NAP .81 Thyrotropin-releasing hormone .....................82 Vasoactive intestinal peptide (VIP). ...............82 Neurotrophic factors ..............83 Activity-dependent neurotrophic factor ..........83 Angiogenesis growth factor-1 83 Bone morphogenetic proteins 83 Brain-derived neurotrophic factor..................84 Ciliary neurotrophic factor .....84 Fibroblast growth factors.......85 Glial cell line-derived neurotrophic factor .......85 Insulin-like growth factor ......86 Nerve growth factor..............86 Neurotrophins......................87 Osteogenic protein-1 ............87 Pigment epithelium-derived factor.................87 Transforming growth factor- b1......................88Vascular endothelial growth factor.................88 Neurotrophic factor-related neuroprotective agents ................88 Colivelin..88 Gambogic amide .............88 Inosine ...89 Meteorin .89 Oxygen-regulated protein 150 kD (ORP150) .....................89 Prosaptide ......................89 Siagoside (GM1 ganglioside)....................90 Nicotine and nicotinic receptor agonists .......90 Nitric oxide-based Neuroprotection ..............92 Nitric oxide synthase inhibitors .....................92 Nitric oxide mimetics ............92 Nootropics ......93 Piracetam94 Nutraceuticals and food constituents............94 Creatine......94 Curcumrin/ curry..................95 Glyceryltriacetate.................95 Green tea.....96 Nicotinamide 96 Resveratrol/ red wine ...........96 Osmotic diuretics ...................97 Mannitol......97 Osteopontin.98 Oxygen therapeutics ..............98 Oxygen carriers ...................98 Hemoglobin-based oxygen carriers................99 Perfluorocarbons ..................99 Hyperbaric oxygen therapy...100 PPARs as drug targets for neuroprotection .100 Riluzole .........101 Role of RNA interference in neuroprotection......................101 Signaling pathway activator.101 Fructose-1,6-bisphosphate ...101 Sir 2 group of proteins .........102 Statins ..........102 Steroids ........103 Dehydroepiandrosterone ......103 HF0220.......103 Sulforaphane.104 Tauroursodeoxycholic acid...104 Tetanus toxin as a neuroprotective agent ...104 Uncoupling protein 2............105 Vaccines as neuroprotectives......................105 - 6 - Non-pharmacological approaches to neuroprotection........105 Environmental enrichment....105 Hypothermia106 Limitations of hypothermia .....................106 Hypothermic neuroprotection in hypoxia-ischemia............107 Hibernation induced by hydrogen sulfide .......107 Ketogenic diet.....................107 Preconditioning-induced neuroprotection.......108 Hypoxic preconditioning ..108 Moderate stimulation of reactive oxygen species ..............109 Chemical preconditioning 109 Transcranial magnetic stimulation ................109 Electrical fields for improvement of cerebral function in neurodegeneration .... 110 Neuroprotective effect of exercise ................110 Hibernation and neuroprotection ..................111 Suspended animation and neuroprotection ....111 3. Neuroprotection in Cerebrovascular Disease ............... 113 Introduction.113 Epidemiology of stroke ........113 Pathophysiology of cerebral ischemia .........114 Calcium overload ................114 Ion channel dysfunction in stroke .................115 Role of oxygen free radicals in cerebral ischemia...................115 Role of Nitric oxide (NO) in cerebral ischemia 115 Glutamate as a marker of stroke ..................115 Cerebral edema in stroke .....116 Gene expression in response to cerebral ischemia .................116 Induction of heat shock proteins in stroke .....116 Role of cytokines and adhesion molecules in stroke ...............117 Tumor necrosis factor (TNF)- a ................117Interleukin (IL)-1 and IL-6 .....................117 Adhesion molecules ........117 DNA damage and repair in cerebral ischemia .118 Role of neurotrophic factors..118 Problems requiring investigation of the role of NTFs in stroke .................. 119 Role of Poly(ADP-ribose) polymerase (PARP) gene.................119 Role of protease-activated receptor 1 ...........119 Reperfusion injury after cerebral ischemia .119 Neuroprotection according to zones in cerebral infarction.120 Zone of ischemic infarction...120 Penumbra ...120 Current management of stroke ...................121 Neuroprotection in stenosis of intracranial arteries ................121 Neuroprotective therapies for stroke ..........122 Agents in research/preclinical stage for neuroprotection in stroke.................. 123 Acid-sensing ion channel blockers ................124 AMPA receptor antagonists as neuroprotectives for stroke ......125 Zonampanel ..................125 Anti-apoptotic neuroprotectives ...................125 NIM811..125 Creatine as neuroprotective in stroke.......126 Lithium as a neuroprotective in stroke .....126 TUDCA as a neuroprotective in stroke......126 Anti-HMGB1 monoclonal antibody.................127 Antioxidant approaches........127 Dehydroascorbic acid......127 Tocotrienols...................128 Carnosine as a neuroprotective in stroke..128 Antiglutamate compounds....129 202W92.129 AR-R15896AR................129 MRZ 2/576 ....................129 L-Phenylalanine .............130 Arimoclomol for stroke.........130 Cardiac glycosides as neuroprotectives in stroke ...................130 Clenbuterol .130 Cox-2 inhibitors for ischemic stroke ..............131 Enoxaparin..131 Estrogen for stroke..............131 Granulocyte-macrophage colony-stimulating factor for cerebral ischemia ....... 133 - 7 - Histamine H2-receptor antagonists ...............133 Inosine for stroke................133 Intravenous immunoglobulin as neuroprotective in stroke .134 Insulin-like growth factor-I...134 Ischemic preconditioning for neuroprotection in stroke ..........134 Ketone bodies.....................135 Minalocorticoid receptor blockade for neuroprotection............136 Multifunctional neuroprotective agents..........136 Neuroserpin as a neuroprotective in stroke....136 N-2-mercaptopropionyl glycine ....................137 NeuroAid.....137 Neurotrophic factors as neuroprotectives for stroke ...............137 AX200 ...137 Brain-derived neurotrophic factor ............138 Neuregulin-1 .................138 NO-based strategies for neuroprotection in cerebral ischemia .138 Peroxisome proliferator-activated receptor- g agonists ............139PGE2 EP2 receptor activation 139 Pioglitazone for reduction of stroke risk in diabetes ...............139 Progesterone ......................139 Proteosome inhibitors ..........140 Statins for stroke prevention 140 Thrombosis inhibitors ..........140 Aspirin ...141 Clopidogrel....................141 Dipyridamole .................141 CBL1309 141 SB-239063..142 Sildenafil....142 Src receptor blockade ..........142 Stroke vaccine ....................143 SUN N4057 .143 Tiagabine ....143 Topiramate..143 Zonisamide .144 Neuroprotectives in reperfusion injury ..........144 Non-pharmacological neuroprotective therapies for stroke......145 Preconditioning for neuroprotection against cerebral ischemia.................. 145 Hypothermia for neuroprotection in acute stroke ..............145 Hyperbaric oxygen therapy for neuroprotection in acute stroke................ 146 Infrared laser therapy for ischemic stroke 147 Neurorehabilitation in relation to neuroprotection in stroke147 Cell therapy for stroke .........147 Gene therapy for neuroprotection in cerebrovascular disease..148 Neuroprotective genetic vaccine..............149 COX-1/PGIS and COX-1 gene transfer in cerebral ischemia ..................... 150 Transfer of the bcl-2 gene for neuroprotection in cerebral ischemia .......... 150 Neuroglobin gene therapy ......................150 Neuroprotective therapies for cerebral ischemia: clinical trials 150 Albumin .152 Free radical scavengers...152 DP-b99 ..154 Erythropoietin as a neuroprotective in stroke ...................154 MaxiPost (BMS-204352)..154 Minocycline for neuroprotection in stroke ......154 Perindopril....... |
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