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NEUROSURGICAL ANESTHESIA

Mild Hypothermia, but Not Propofol, Is Neuroprotective in Organotypic Hippocampal Cultures

Department of Anesthesia and Perioperative Care, University of California, San Francisco.

Address correspondence and reprint requests to Philip E. Bickler, MD, PhD, Sciences 255, Box 0542, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143–0542. Address e-mail to bicklerp{at}anesthesia.ucsf.edu

The neuroprotective potency of anesthetics such as propofol compared to mild hypothermia remains undefined. Therefore, we determined whether propofol at two clinically relevant concentrations is as effective as mild hypothermia in preventing delayed neuron death in hippocampal slice cultures (HSC). Survival of neurons was assessed 2 and 3 days after 1 h oxygen and glucose deprivation (OGD) either at 37°C (with or without 10 or 100 µM propofol) or at an average temperature of 35°C during OGD (mild hypothermia). Cell death in CA1, CA3, and dentate neurons in each slice was measured with propidium iodide fluorescence. Mild hypothermia eliminated death in CA1, CA3, and dentate neurons but propofol protected dentate neurons only at a concentration of 10 µM; the more ischemia vulnerable CA1 and CA3 neurons were not protected by either 10 µM or 100 µM propofol. In slice cultures, the toxicity of 100 µM N-methyl-D-aspartate (NMDA), 500 µM glutamate, and 20 µM -amino-5-methyl-4-isoxazole propionic acid (AMPA) was not reduced by 100 µM propofol. Because propofol neuroprotection may involve gamma-aminobutyric acid (GABA)-mediated indirect inhibition of glutamate receptors (GluRs), the effects of propofol on GluR activity (calcium influx induced by GluR agonists) were studied in CA1 neurons in HSC, in isolated CA1 neurons, and in cortical brain slices. Propofol (100 and 200 µM, approximate burst suppression concentrations) decreased glutamate-mediated [Ca²⁺]_i increases ([Ca²⁺]_i) responses by 25%–35% in isolated CA1 neurons and reduced glutamate and NMDA [Ca²⁺]_i in acute and cultured hippocampal slices by 35%–50%. In both CA1 neurons and cortical slices, blocking GABA_A receptors with picrotoxin reduced the inhibition of GluRs substantially. We conclude that mild hypothermia, but not propofol, protects CA1 and CA3 neurons in hippocampal slice cultures subjected to oxygen and glucose deprivation. Propofol was not neuroprotective at concentrations that reduce glutamate and NMDA receptor responses in cortical and hippocampal neurons.

IMPLICATIONS: The neuroprotective qualities of propofol are controversial. In rat hippocampal slice cultures, mild hypothermia (35°C), but not propofol, was protective after oxygen and glucose deprivation. Failure of propofol neuroprotection in this model may be related to relatively modest inhibition of glutamate receptor responses and excitotoxicity.

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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