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

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 ([Ca 2+ ] 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 [Ca 2+ ] i were monitored after mechanical injury or L-glutamate exposure by ratiometric imaging of sodiumbinding 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 sodiumcalcium exchanger with 2-[2-[4-(4-Nitrobenzyloxy)-phenyl]ethyl]isothiourea mesylate (KB-R7943) reduced [Ca 2+ ] 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.

Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal–astrocytic co-cultures

“…For instance, direct strain to astrocytes has been shown to increase cytosolic calcium from both extracellular and intracellular sources, which increased with more severe insults; however, these experiments did not independently isolate the effects of strain and strain rate (Rzigalinski et al, 1998;Floyd et al, 2001;Neary et al, 2003). Additionally, mechanical stress may open stretch-activated ion channels, leading to increased intracellular calcium (Bowman et al, 1992;Rzigalinski et al, 1998;Floyd et al, 2005). Thus, astrocytes may possess mechanisms to directly respond to mechanical stress and the associated deformation in both physiological and pathophysiological settings.…”

Glutamate Neurotransmission in Rodent Models of Traumatic Brain Injury

“…[87][88][89] CCI models demonstrate an early and consistent loss of EAAT2 protein in the ipsilateral cortex beginning 4-6 h after injury and persisting past 72 h. 86 In studies utilizing lateral FPI, EAAT2 expression in the ipsilateral cortex may not change during the first 24 h; however, decreases in the 266 DORSETT ET AL.…”

Intensive Care Treatment in Traumatic Brain Injury

“…Artmış glutamat nöron ve astrositlerdeki reseptörleri uyararak Ca +2, Na + ve K + akışına neden olmaktadır (13). Bu durum katabolik süreçleri tetikleyip hücre hasarına neden olmakta, kan-beyin bariyerini de bozmaktadır.…”