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General anesthetics reduce neuronal death caused by focal cerebral ischemia in rodents and by in vitro ischemia in cultured neurons and brain slices. However, in intact animals, the protective effect may enhance neuronal survival for only several days after an ischemic injury, possibly because anesthetics prevent acute but not delayed cell death. To further understand the mechanisms and limitations of volatile anesthetic neuroprotection, the authors developed a rat hippocampal slice culture model of cerebral ischemia that permits assessment of death and survival of neurons for at least 2 weeks after simulated ischemia.Survival of CA1, CA3, and dentate gyrus neurons in cultured hippocampal slices (organotypic slice culture) was examined 2–14 days after 45 min of combined oxygen–glucose deprivation at 37°C (OGD). Delayed cell death was serially measured in each slice by quantifying the binding of propidium iodide to DNA with fluorescence microscopy.Neuronal death was greatest in the CA1 region, with maximal death occurring 3–5 days after OGD. In CA1, cell death was 80 ± 18% (mean ± SD) 3 days after OGD and was 80–100% after 1 week. Death of 70 ± 16% of CA3 neurons and 48 ± 28% of dentate gyrus neurons occurred by the third day after OGD. Both isoflurane (1%) and the N-methyl-d-aspartate antagonist MK-801 (10 μm) reduced cell death to levels similar to controls (no OGD) for 14 days after the injury. Isoflurane also reduced cell death in CA1 and CA3 caused by application of 100 but not 500 μm glutamate. Cellular viability (calcein fluorescence) and morphology were preserved in isoflurane-protected neurons.In an in vitro model of simulated ischemia, 1% isoflurane is of similar potency to 10 μm MK-801 in preventing delayed cell death. Modulation of glutamate excitotoxicity may contribute to the protective mechanism.