Propofol protection of sodium-hydrogen exchange activity sustains glutamate uptake during oxidative stress

We investigated the role of intracellular pH in protection by propofol of glutamate uptake during oxidative stress. Exposure of primary astrocyte cultures to tert-butylhydroperoxide (t-BOOH, 300 muM) decreased the initial rate of Na-dependent glutamate uptake. Either propofol or alpha -tocopherol, administered 30 min after t-BOOH, attenuated this transport inhibition. These lipophilic antioxidants. protected glutamate uptake whether the medium contained 25 mM bicarbonate or was nominally bicarbonate-free. t-BOOH also inhibited Na/H exchanger isoform. I (NHE1) activation by intracellular protons and propofol prevented this inhibition. Blockade of NHE1 by the potent antagonist, 5-(N-ethyl-N-isopropyl) amiloride (I muM), abolished the protective effects of small concentrations of propofol (1 muM) and a-tocopherol (40 muM) on glutamate uptake during oxidative stress in bicarbonate-free medium. 5-(Nethyl-N-isopropyl) amiloride had no effect on antioxidant rescue of glutamate transport in medium containing 25 mM bicarbonate. These results indicate that regulation of intracellular pH may contribute to neuroprotection by propofol and other lipophilic antioxidants. Propofol concentrations that are associated with anesthesia and neuroprotection may prevent intracellular acidification during oxidative stress by preserving the NHE1 response to cytosolic protons. However, if intracellular acidification occurs nonetheless, then propofol protection of glutamate uptake activity becomes less effective and the extracellular glutamate concentration may increase to neurotoxic levels.