ABSTRACT
Excitotoxicity: The Molecular Response to Head Injury.........................................98 Evidence for Increased Extracellular Glutamate after Traumatic Brain Injury (TBI) and Mechanisms of Release ...........................................................98 Summary of Preclinical Studies on Glutamate Receptor Antagonists ................99 Novel Concepts in Glutamate Excitotoxicity after TBI: Role of Astrocytic Glutamate Transporters and Gap Junctions.........................................................99 Role of Calpains in Excitotoxicity .................................................................... 100 GABAergic Excitotoxicity ................................................................................ 101 Controversy regarding the Contribution of Glutamatergic Excitotoxicity to Secondary Neuronal Injury ........................................................................... 102 Therapeutic Targets of Excitotoxicity ............................................................... 103
Apoptosis: The Cellular Response to Head Injury................................................. 104 Introduction ....................................................................................................... 104 Overview of the Apoptosis Pathways ................................................................ 104
Caspase-Dependent Apoptosis ..................................................................... 104 Caspase-Independent Apoptosis ................................................................... 106 Regulation of Apoptosis ............................................................................... 106
Evidence for Apoptosis after TBI ..................................................................... 106 Necroptosis ........................................................................................................ 107
Mitochondrial Injury: An Organelle Bridge from Molecular to Cellular Pathology .... 108 Structure and Function of Mitochondria ........................................................... 108 Interconnectivity of Mitochondria and Other Organelles ................................. 109 Subcellular Causes of Mitochondrial Injury ..................................................... 109 Mitochondrial Injury and Reactive Oxygen Species ......................................... 110 Cyclosporine as a Therapeutic for Mitochondrial Injury .................................. 111
Excitotoxicity-Induced Endoplasmic Reticulum Stress and TBI: An Emerging Therapeutic Target ................................................................................................. 111
Excitotoxicity-the cascade of intracellular events initiated by excessive stimulation by neurotransmitters leading to intracellular calcium overload-is hypothesized to play an important role in mediating secondary neuronal injury after traumatic brain injury (TBI). While a variety of neurotransmitters could potentially trigger excitotoxic cell injury, glutamate is thought to be the primary contributor because of its potent effect on increasing intracellular calcium through ionotropic receptors (primarily NMDAR, but also kainate and calcium-permeable AMPAR). Microdialysis studies in rodents after both fluid percussion injury and controlled cortical impact have demonstrated a substantial increase in extracellular glutamate proportional to the severity of injury.1,2 A number of clinical observations also support the hypothesis that TBI increases extracellular glutamate. Multiple reports analyzing glutamate levels in cerebrospinal fluid (CSF) with the elevation often persisting beyond 1 week after injury.3,4 A prospective microdialysis study in patients suffering severe TBI showed an increase in extracellular glutamate in over 75% of patients; interestingly, values normalized over the course of 120 hours in 60% of these patients, but persistent elevations of extracellular glutamate were associated with increased mortality.5
