Mild hypothermia, but not propofol, is neuroprotective in organotypic hippocampal cultures

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 37degreesC (with or without 10 or 100 muM propofol) or at an average temperature of 35degreesC 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 muM; the more ischemia vulnerable CA1 and CA3 neurons were not protected by either 10 muM or 100 muM propofol. In slice cultures, the toxicity of 100 muM N-methyl-D-aspartate (NMDA), 500 muM glutamate, and 20 muM alpha-amino-5-methyl-4-isoxazole propionic acid (AMPA) was not reduced by 100 muM 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 muM, approximate burst suppression concentrations) decreased glutamate-mediated [Ca2+](i) ncreases (Delta[Ca2+](i) responses by 25%-35% in isolated CA1 neurons and reduced glutamate and NMDA Delta[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 CAI 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.