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 g lutamate uptake during oxidative stress. Exposure of primary astrocyte cult ures to tert-butylhydroperoxide (t-BOOH, 300 muM) decreased the initial rat e of Na-dependent glutamate uptake. Either propofol or alpha -tocopherol, a dministered 30 min after t-BOOH, attenuated this transport inhibition. Thes e lipophilic antioxidants. protected glutamate uptake whether the medium co ntained 25 mM bicarbonate or was nominally bicarbonate-free. t-BOOH also in hibited Na/H exchanger isoform. I (NHE1) activation by intracellular proton s and propofol prevented this inhibition. Blockade of NHE1 by the potent an tagonist, 5-(N-ethyl-N-isopropyl) amiloride (I muM), abolished the protecti ve effects of small concentrations of propofol (1 muM) and a-tocopherol (40 muM) on glutamate uptake during oxidative stress in bicarbonate-free mediu m. 5-(Nethyl-N-isopropyl) amiloride had no effect on antioxidant rescue of glutamate transport in medium containing 25 mM bicarbonate. These results i ndicate that regulation of intracellular pH may contribute to neuroprotecti on by propofol and other lipophilic antioxidants. Propofol concentrations t hat are associated with anesthesia and neuroprotection may prevent intracel lular acidification during oxidative stress by preserving the NHE1 response to cytosolic protons. However, if intracellular acidification occurs nonet heless, then propofol protection of glutamate uptake activity becomes less effective and the extracellular glutamate concentration may increase to neu rotoxic levels.