antioxidant bilirubin. Hsp70 inhibits NF-κB signaling and intrinsic apoptotic pathways (Calabrese et al., 2008). In the setting of TBI, each of those neuroprotective systems in the brain becomes overwhelmed, and cell damage arises from free-radical–mediated lipid peroxidation. protein and DNA oxidation, and inhibition of the mitochondrial electron-transport chain.


In general, an inflammatory response in the brain differs from that in other organs. It is exemplified by a more modest and delayed recruitment of leukocytes into the brain than into peripheral organs (Lucas et al., 2006). Brain microglia, in contrast, are activated and release inflammatory mediators beginning within minutes to hours after TBI (Lucas et al., 2006). The mediators often express neurotoxic and neuroprotective properties (Morganti-Kossmann et al., 2007). For example, cytokines may either promote damage or support recovery processes; in some cases, cytokines, such as interleukin-6, may perform both functions (Morganti-Kossmann et al., 2007).


Collectively, the pathogenic cascade of events described in the preceding paragraphs culminates in death of neurons and glia and white matter degeneration. Distinct anatomic patterns of cell death that accompany TBI are evident in neuronal and glial populations and reflect both apoptosis and necrosis (Raghupathi, 2004; Bramlett and Dietrich, 2007). Necrotic death and apoptotic cell death of neurons and glia have been identified in contused areas, the tissue bordering a contusion, and subcortical regions, including the hippocampus, cerebellum, and thalamus (Raghupathi et al., 2000; Raghupathi, 2004; Yakovlev and Faden, 2004). In the case of the contused cortex, gross loss of neurons culminates in a distinct lesion, enlarges with time postinjury, and coincides with progressive atrophy of gray and white matter (Bramlett and Dietrich, 2007).


The vulnerability of astrocytes to TBI has also been recently reconsidered (Floyd and Lyeth, 2007). Historically, the dogma has been that astrocytes are more resistant to injury than neurons (Lukaszevicz et al., 2002). Beyond the characteristic swelling that is seen (Castejon, 1998), those cells show an early injury response that coincides with regional patterns of neuronal vulnerability. Kinetic studies suggest that loss of astrocytes precedes neuronal injury suggesting that early impairment of astrocytes contributes to neuronal death (Floyd and Lyeth, 2007).


Astrocytes play time-dependent diverse roles in TBI (Chen and Swanson, 2003); here we consider their involvement in the acutely injured brain (modulation of extracellular glutamate and K+ concentrations, scavenging of ROSs, and inflammation) and during wound healing (glial scar formation, restoration of the blood–brain barrier, and growth factor production) (Chen and Swanson, 2003).


Neurons depend on astrocytes for their survival in an acutely injured brain (Chen and Swanson, 2003). After brain injury, glutamate is cleared from the extracellular space by Na+-dependent glutamate transporters that are localized on astrocytes. Thus, astrocytes are thought to play a critical role in maintaining extracellular glutamate concentrations below toxic levels. Glutamate transport occurs across a steep concentration gradient with much higher concentrations (1–10 mM) in neurons and glia and lower concentrations (less than 10 mM) in the extracellular compartment. That gradient is overcome by the coupling of the intracellular influx of glutamate ions to the inward movement of 3 Na+ ions and 1 H+ ion and the outward movement of 1 K+, a process that shifts energy expenditure from neurons to astrocytes. Glutamate transporters can move substrate both inward and outward.



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