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ANESTHETIC PHARMACOLOGY

Propofol Protection of Sodium-Hydrogen Exchange Activity Sustains Glutamate Uptake During Oxidative Stress

Rina Daskalopoulos, BSc^*, Jasminka Korcok, BSc^*, Parviz Farhangkhgoee, DVM, Morris Karmazyn, PhD, Adrian W. Gelb, MB, and John X. Wilson, PhD^*

Departments of *Physiology, Pharmacology and Toxicology, and Anaesthesia, University of Western Ontario, London, Ontario, Canada

Address correspondence and reprint requests to Dr. John X. Wilson, Department of Physiology, University of Western Ontario, London, Ontario, N6A 5C1, Canada. Address e-mail to John.Wilson{at}fmd.uwo.ca

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 µM) decreased the initial rate of Na-dependent glutamate uptake. Either propofol or -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 1 (NHE1) activation by intracellular protons and propofol prevented this inhibition. Blockade of NHE1 by the potent antagonist, 5-(N-ethyl-N-isopropyl) amiloride (1 µM), abolished the protective effects of small concentrations of propofol (1 µM) and -tocopherol (40 µM) on glutamate uptake during oxidative stress in bicarbonate-free medium. 5-(N-ethyl-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.

IMPLICATIONS: Anesthetic concentrations of propofol maintain the capacity of brain cells to extrude protons during oxidative stress. However, if intracellular acidification occurs nonetheless, then propofol’s protection of glutamate clearance mechanisms from oxidative damage becomes attenuated, and extracellular glutamate concentration may increase to neurotoxic levels.

This article has been cited by other articles:

				J. R. Feiner, P. E. Bickler, S. Estrada, P. H. Donohoe, C. S. Fahlman, and J. A. Schuyler Mild Hypothermia, but Not Propofol, Is Neuroprotective in Organotypic Hippocampal Cultures Anesth. Analg., January 1, 2005; 100(1): 215 - 225. [Abstract] [Full Text] [PDF]

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999