MOLECULAR AND CELLULAR BIOLOGY OF NEUROPROTECTION IN THE CNS
CONTENTS I NEURONAL CELL DEATH— OVERVIEW OF BASIC MECHANISMS 1 EXCITATORY AMINO ACID NEUROTOXICITY HISTORICAL PERSPECTIVE CLINICAL RELEVANCE OF EXCITATORY AMINO ACID NEUROTOXICITY EPILEPSY TRAUMATIC BRAIN INJURY HYPOXIA/ISCHEMIA NEURODEGENERATIVE DISEASES INTOXICATION WITH EXOGENOUS EXCITATORY AMINO ACIDS IMPLICATION OF DISTINCT GLUTAMATE RECEPTOR CLASSES IN EXCITOTOXICITY IONIC DEPENDENCE OF EXCITOTOXIC CELL DAMAGE MITOCHONDRIAL DYSFUNCTION THE ROLE OF REACTIVE OXYGEN SPECIES IN EXCITOTOXICITY ROLE OF NITRIC OXIDE AND OTHER REACTIVE NITROGEN SPECIES IN EXCITOTOXICITY EXCITOTOXICITY, CALCIUM LOADING AND APOPTOSIS KEY SIGNALING PLAYERS IN NEURONAL APOPTOSIS CONCLUSIONS 2 NEURONAL SURVIVAL AND CELL DEATH SIGNALING PATHWAYS ABSTRACT INTRODUCTION DEATH RECEPTOR-MEDIATED NEURONAL APOPTOSIS SIGNAL TRANSDUCTION PATHWAYS NUCLEAR SIGNALING PATHWAYS P53-MEDIATED CELL DEATH SIGNALING PATHWAYS BCL-2 FAMILY MEMBERS AND MITOCHONDRIAL INTEGRITY PROTEOLYTIC ENZYMES CALPAINS ABBREVIATIONS 3 DETRIMENTAL AND BENEFICIAL EFFECTS OF INJURY-INDUCED INFLAMMATION AND CYTOKINE EXPRESSION IN THE NERVOUS SYSTEM GLIAL CELL POPULATIONS IN THE CENTRAL NERVOUS SYSTEM ENTRY OF INFLAMMATORY CELLS INTO THE CNS: THE BLOOD-BRAIN-BARRIER AND IMMUNOLOGICAL CELL ADHESION MOLECULES INFLAMMATION AND CNS INJURY BENEFICIAL EFFECTS OF NEUROINFLAMMATION ACKNOWLEDGEMENT 4 CELLULAR AND MOLECULAR DETERMINANTS OF GLIAL SCAR FORMATION DEVELOPMENT OF THE SCAR AXON REGENERATION AND SCARRING CYTOKINES AND SCARRING TROPHIC REGULATION OF THE SCAR PROTEASE REGULATION OF SCARRING THERAPEUTIC MODULATION OF THE SCAR II ION CHANNELS, RECEPTORS AND SIGNALING PATHWAYS 5 NA+ CHANNELS AND CA2+ CHANNELS OF THE CELL MEMBRANE AS TARGETS OF NEUROPROTECTIVE SUBSTANCES NA+ CHANNELS NA+ CHANNEL BLOCKERS AS NEUROPROTECTIVE AGENTS CA2+ CHANNELS ACKNOWLEDGEMENTS 6 INTRACELLULAR CA2+ HANDLING CYTOSOLIC CA2+ BUFFERING CA2+ BUFFERING AND NEUROPROTECTION THE ENDOPLASMIC RETICULUM CA2+ STORE THE ENDOPLASMIC RETICULUM AND NEUROPROTECTION MITOCHONDRIA AND CA2+ HOMEOSTASIS MITOCHONDRIA, NEUROTOXICITY AND NEUROPROTECTION FUTURE CHALLENGES 7 NEUROPROTECTIVE ACTIVITY OF METABOTROPIC GLUTAMATE RECEPTOR LIGANDS CHEMICAL STRUCTURES AND RECEPTOR PROFILE OF NEUROPROTECTIVE MGLUR LIGANDS PHYSICO-CHEMICAL AND PHARMACOKINETIC PROPERTIES OF NEUROPROTECTIVE MGLUR LIGANDS GROUP-I MGLURS AS TARGETS FOR NEUROPROTECTIVE DRUGS NEUROPROTECTION MEDIATED BY GROUP-II MGLURS ROLE OF GROUP-III MGLURS IN NEUROPROTECTION CONCLUSIONS AND OUTLOOK 8 A ROLE FOR GLUTAMATE TRANSPORTERS IN NEURODEGENERATIVE DISEASES THE NA+/K+-DEPENDENT HIGH AFFINITY GLUTAMATE TRANSPORTERS LOCALIZATION OF GLUTAMATE TRANSPORTERS FUNCTIONAL PROPERTIES, STOICHIOMETRY AND KINETICS OF THE GLUTAMATE TRANSPORTERS GLUTAMATE TRANSPORTER TOPOLOGY ROLE OF GLUTAMATE TRANSPORTERS IN THE EXCITATORY NEUROTRANSMISSION REGULATION OF GLUTAMATE TRANSPORTERS GLUTAMATE TRANSPORTERS IN DISEASE STATES CONCLUDING REMARKS 9 PURINES AND NEUROPROTECTION ADENOSINE ADENOSINE RECEPTORS A2A RECEPTORS 10 HEAT SHOCK PROTEINS AND NEUROPROTECTION WHERE AND WHEN IS HSP70 EXPRESSED? CORRELATIVE EVIDENCE FOR A NEUROPROTECTIVE ROLE NEUROPROTECTION WITH HSP70 OVEREXPRESSION POTENTIAL MECHANISMS OF PROTECTION CONCLUSION ACKNOWLEDGMENTS III NEUROTROPHIC FACTORS AS NEUROPROTECTIVE AGENTS 11 NEUROTROPHINS SUMMARY FROM NEUROTROPHIN PHYSIOLOGY TO THERAPY STRUCTURE AND PHYSIOLOGICAL FUNCTIONS OF NEUROTROPHINS AND THEIR RECEPTORS NEUROTROPHINS IN ANIMAL MODELS OF PATHOLOGICAL SITUATIONS AND CLINICAL TRIALS NON-NEUROPROTECTIVE AND SIDE EFFECTS OF NEUROTROPHINS POTENTIAL IMPROVEMENTS OF NEUROTROPHIN THERAPY 12 FIBROBLAST GROWTH FACTORS AND NEUROPROTECTION INTRODUCTION—FIBROBLAST GROWTH FACTORS (FGFS) AND FGF RECEPTORS DISTRIBUTION OF FGFS IN ADULT BRAIN FGFS AND NEURONAL DEVELOPMENT UPREGULATION OF FGFS AFTER BRAIN INJURY NEUROPROTECTIVE EFFECTS OF FGF2 FGFS AND GLIA NEUROPROTECTIVE MECHANISMS OF FGF2 SUMMARY AND CONCLUSIONS 13 TGF-?S AND THEIR ROLES IN THE REGULATION OF NEURON SURVIVAL TGF-?S: A BRIEF OVERVIEW OF THEIR MOLECULAR BIOLOGY, BIOCHEMISTRY AND SIGNALING EXPRESSION OF TGF-?S AND T?RS IN THE NERVOUS SYSTEM TGF-?S AND THE REGULATION OF PROLIFERATION, SURVIVAL AND DIFFERENTIATION OF NEURONS REGULATION OF NEURON SURVIVAL AND MAINTENANCE BY MEMBERS OF THE TGF-? SUPERFAMILY OTHER THAN TGF-?S PROPER 14 VASCULAR ENDOTHELIAL GROWTH FACTOR THE MEMBERS OF THE VEGF FAMILY REGULATION OF VEGF AND VEGF RECEPTOR EXPRESSION PLEIOTROPIC ACTION OF VEGF IN THE CNS INTRACELLULAR SIGNALING EVENTS IV ADVANCES IN DRUG DELIVERY TO CNS NEURONS 15 BLOOD-BRAIN BARRIER DRUG TARGETING ENABLES NEUROPROTECTION IN BRAIN ISCHEMIA FOLLOWING DELAYED INTRAVENOUS ADMINISTRATION OF NEUROTROPHINS BLOOD-BRAIN BARRIER, NEUROTROPHINS AND NEUROLOGICAL DISEASE CHIMERIC PEPTIDE TECHNOLOGY TARGETING CHIMERIC NEUROTROPHIC FACTORS TO THE BRAIN TARGETING GENE THERAPEUTICS TO THE BRAIN DRUG TARGETING TO THE HUMAN BRAIN 16 INVASIVE DRUG DELIVERY VECTORS IN GENE THERAPY DIRECT DNA DELIVERY AND SYNTHETIC NONVIRAL VECTORS VIRAL VECTORS AND GENE DELIVERY HERPES SIMPLEX VIRAL VECTORS ADENOVIRAL VECTORS ADENO-ASSOCIATED VIRAL VECTOR (AAV) RETROVIRUS BIOLOGY OF RETROVIRUSES MOLONEY MURINE LEUKEMIA VIRUS AND LENITVIRUS BASED VECTORS RETROVIRAL GENE TRANSFER EX VIVO RETROVIRAL GENE TRANSFER IN VIVO RETROVIRAL VECTOR SAFETY V NEUROPROTECTIVE STRATEGIES IN ANIMAL AND IN VITRO MODELS OF NEURONAL DAMAGE 17 ISCHEMIA AND STROKE EPIDEMIOLOGICAL DATA GOBAL VS FOCAL ISCHEMIA ANIMAL MODELS OF CEREBRAL ISCHEMIA IN VITRO MODELS OF CEREBRAL ISCHEMIA IMPORTANCE OF PHYSIOLOGIC PARAMETERS FOR STROKE OUTCOME PATHOPHYSIOLOGICAL CASCADES FOLLOWING CEREBRAL ISCHEMIA GLUTAMATE RECEPTORS AND EXCITOTOXICITY TISSUE ACIDOSIS PROTEIN SYNTHESIS AND EARLY GENE EXPRESSION MOLECULAR MECHANISMS EXPERIMENTAL EVIDENCE FOR CASPASE-MEDIATED CELL DEATH FOLLOWING CEREBRAL ISCHEMIA CASPASE INHIBITION PROTECTS FROM CEREBRAL ISCHEMIA 18 NEUROPROTECTIVE STRATEGIES IN ALZHEIMER'S DISEASE WHAT IS THE CAUSE OF AD? AD GENETICS AND BIOCHEMISTRY NEUROTOXICOLOGY OF A? AD RISK FACTORS MOUSE MODELS OF AD CLINICAL AD THERAPY EXPERIMENTAL AD THERAPIES AD PREVENTION FINAL REMARKS