Lysophospholipids (LPLs) are important interme-diates in the synthesis and degradation of membrane phospho-lipids. Here we show that certain LPLs, particularly lysophos-phatidylcholine and lysophosphatidylinositol, prevent neuronal death both in an in vivo model of transient global ischemia and in an in vitro model of excitotoxicity using primary cultures of cerebellar granule cells exposed to high extracellular concentrations of glutamate (20-40 mol/L). The intravenous injection of lysophosphatidylcholine or lysophosphatidylinositol at a concentration of 200 nmol/kg induced a survival of CA1 py-ramidal neurons as high as approximately 95%, even when the treatment was started 30 minutes after 15-minute global isch-emia. In contrast, lysophosphatidic acid induced no protection. This work also provides evidence that a pretreatment with ly-sophosphatidylcholine or lysophosphatidylinositol (200 nmol/kg) injected as long as 3 days before a severe 6-minute ischemia provided a potent tolerance against neurodegenera-tion. Neuroprotection was also observed in in vitro experiments with LPLs. Taken together, in vivo and in vitro data suggest a potential therapeutic use of LPLs as antiischemic compounds. The potential role of 2P-domain K + channels as targets of LPLs in this potent neuroprotective effect is discussed.