title: Mild hypothermia, but not propofol, is neuroprotective in organotypic hippocampal cultures.
abstract: 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 degrees C (with or without 10 or 100 microM propofol) or at an average temperature of 35 degrees 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 microM; the more ischemia vulnerable CA1 and CA3 neurons were not protected by either 10 microM or 100 microM propofol. In slice cultures, the toxicity of 100 muM N-methyl-D-aspartate (NMDA), 500 microM glutamate, and 20 microM alpha-amino-5-methyl-4-isoxazole propionic acid (AMPA) was not reduced by 100 microM 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 microM, approximate burst suppression concentrations) decreased glutamate-mediated [Ca2+]i increases (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 GABAA 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.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco.
authors.forename: John R
authors.initials: JR
authors.lastname: Feiner
authors.forename: Philip E
authors.initials: PE
authors.lastname: Bickler
authors.forename: Sergio
authors.initials: S
authors.lastname: Estrada
authors.forename: Paul H
authors.initials: PH
authors.lastname: Donohoe
authors.forename: Christian S
authors.initials: CS
authors.lastname: Fahlman
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Schuyler
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology*; D007036:Hypothermia, Induced; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D009924:Organ Culture Techniques; D010852:Picrotoxin / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects
chemical_list: D018686:Anesthetics, Intravenous; D002118:Calcium; D018756:GABA Antagonists; D018696:Neuroprotective Agents; D010852:Picrotoxin; D015742:Propofol; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate