Mechanical strain injury increases intracellular sodium and reverses Na+/Ca2+ exchange in cortical astrocytes

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Abstract
Traditionally, astrocytes have been considered less susceptible to injury than neurons. Yet, we have recently shown that astrocyte death precedes neuronal death in a rat model of traumatic brain injury (TBI) (Zhao et al.: Glia 44:140–152, 2003 ). A main mechanism hypothesized to contribute to cellular injury and death after TBI is elevated intracellular calcium ([Ca2+]i). Since calcium regulation is also influenced by regulation of intracellular sodium ([Na+]i), we used an in vitro model of strain‐induced traumatic injury and live‐cell fluorescent digital imaging to investigate alterations in [Na+]i in cortical astrocytes after injury. Changes in [Na+]i, or [Ca2+]i were monitored after mechanical injury or L‐glutamate exposure by ratiometric imaging of sodium‐binding benzofuran isophthalate (SBFI‐AM), or Fura‐2‐AM, respectively. Mechanical strain injury or exogenous glutamate application produced increases in [Na+]i that were dependent on the severity of injury or concentration. Injury‐induced increases in [Na+]i were significantly reduced, but not completely eliminated, by inhibition of glutamate uptake by DL‐threo‐β‐benzyloxyaspartate (TBOA). Blockade of sodium‐dependent calcium influx through the sodium‐calcium exchanger with 2‐[2‐[4‐(4‐Nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate (KB‐R7943) reduced [Ca2+]i after injury. KB‐R7943 also reduced astrocyte death after injury. These findings suggest that in astrocytes subjected to mechanical injury or glutamate excitotoxicity, increases in intracellular Na+ may be a critical component in the injury cascade and a therapeutic target for reduction of lasting deficits after traumatic brain injury.