Phase 2 involves the progressive deterioration of the neural axis that arises from biochemical and molecular events that collectively promote necrotic and apoptotic cell death (Graham et al., 2002; Thompson et al., 2005). The events include release of the excitatory amino acid neurotransmitters, such as glutamate and aspartate; activation of glutamate receptors; influx of calcium into cells and release of calcium from intracellular stores; free-radical generation; and inflammation (Graham et al., 2002; Thompson et al., 2005; Werner and Engelhard, 2007).

In both animal and human studies, TBI results in increased extracellular glutamate concentrations (Schouten, 2007). The increase has been attributed to disruption of the blood–brain barrier and exposure of the brain to humoral-derived glutamate, excessive synaptic release, and decreased glutamate transporter (Yi and Hazell, 2006). Glutamate is the most abundant excitatory neurotransmitter in the brain. In the setting of TBI, an increase in glutamate results in overstimulation of ion-channel–linked and G-protein–linked glutamate receptors. Excessive activation of those ion channels results in prolonged depolarization and ionic imbalance, depletion of ATP stores, and increases in intracellular free calcium that potentially activate numerous pathogenic cascades (Yi and Hazell, 2006).

Intracellular calcium increases rapidly after TBI. That is attributed to an increased influx of Ca2+ from the extracellular compartment and a release of Ca2+ from intracellular stores, including mitochondria. The increase in intracellular Ca2+ leads to activation of intracellular proteases, including calcium-activated neutral proteases (calpains), phospholipases, and endonucleases. Those downstream events mediate cytoskeletal damage, increase intracellular concentrations of free fatty acids, promote free-radical generation, and lead to cell injury and death (Marklund et al., 2006; Werner and Engelhard, 2007).

An important component of the secondary injury cascade results from the generation of reactive oxygen species (ROSs) that include superoxides, hydrogen peroxide, hydroxyl radicals, nitric oxide, and peroxynitrite. Each ROS has an unpaired electron in its outer electron shell and thus is highly reactive and unstable (Calabrese et al., 2008). The excessive production of ROSs is due in part to excitotoxicity, free iron, and interactions between ROSs (Potts et al., 2006). Glutamate-mediated excitotoxicity leads to an increase in intracellular calcium and the subsequent induction of enzymes, such as nitric oxide synthase and xanthine oxidase, that produce free radicals. Mitochondria, when exposed to increased intracellular calcium, become sources of ROSs (Sullivan et al., 2005; Bayir and Kagan, 2008). Accumulation of free iron, resulting from the degradation of heme, catalyzes the formation of superoxide from free oxygen and of the hydroxyl radical from hydrogen peroxide. It is important to note that free radicals such as superoxide and nitric oxide interact with one another to produce other free radicals, including peroxynitrite.

Under physiologic conditions, endogenous antioxidants—including superoxide dismutase, glutathione peroxidase, and catalase—prevent oxidative damage (Potts et al., 2006). Superoxide dismutase catalyzes the conversion of superoxide to hydrogen peroxide, which is further degraded by glutathione peroxidase and catalase to molecular oxygen and water. Low-molecular-weight antioxidants—including glutathione, melatonin, and uric acid—and dietary sources of tocopherols, ascorbic acid and lipoic acid, are also available in the brain.

A group of genes, referred to as vitagenes, function to preserve cellular homeostasis during stress. This family consists of the heat-shock proteins HO-1 and Hsp32. HO-1 confers protection by degrading the pro-oxidant heme and producing biliverdin, the precursor of the

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