Anesthetic concentrations of propofol protect against oxidative stress in primary astrocyte cultures - Comparison with hypothermia

Background: The extracellular concentration of glutamate in the brain incre ases after oxidative damage. This increase may be caused, in part, by chang es in glutamate transport by astrocytes. The authors hypothesized that prop ofol and hypothermia mitigate the effects on astrocytes of oxidative stress . Methods: Primary cultures of rat cerebral astrocytes mere subjected to oxid ative stress by incubation with tert-butyl hydroperoxide for 30 min, follow ed by a 30-90-min washout period. The effects of prophylactic (simultaneous with tert-butyl hydroperoxide application) and delayed (administered 30 mi n after the oxidant) propofol or hypothermia mere determined by measuring t he uptake of glutamate as well as the release of preloaded D-aspartate (a n onmetabolizable analog of glutamate) and endogenous lactate dehydrogenase ( a cytosolic marker). Results: Delayed administration of an anesthetic concentration of propofol (1-3 muM) prevented the inhibition of high-affinity glutamate uptake, stimu lation of D-aspartate release, and increase in lactate dehydrogenase releas e caused by tert-butyl hydroperoxide (1 mM, 37 degreesC). The protective ef fect of propofol (EC50 = 2 muM) on glutamate uptake was 20-fold more potent than that of a-tocopherol (EC50 = 40 muM). Prophylactic hypothermia (28 an d 33 degreesC) also protected astrocytes from tert-butyl hydroperoxide, Del ayed hypothermia was not protective but did not compromise rescue by propof ol, Conclusions: Clinical levels of propofol and hypothermia mitigate the effec ts of oxidative stress on astrocytic uptake and retention of glutamate, wit h propofol having a relatively larger therapeutic window. The ability of th ese treatments to normalize cell transport systems may attenuate the pathol ogic increase in extracellular glutamate at synapses and thus prevent excit otoxic neuronal death.