Addition of the natural gangliosides monosialoganglioside (GM1), disialoganglioside, trisialoganglioside, or tetrasialoganglioside in the range of 10 to 100 microM, but not asialoganglioside lacking the sialic acid moiety, attenuated cortical neuronal apoptosis induced by serum deprivation, ionomycin, or cyclosporin A but not by protein kinase inhibitors (staurosporine, genistein, lavendustin A, or herbimycin A). Coaddition of 100 nM wortmannin, a selective inhibitor of phosphatidylinositol 3-kinase, but not 1 microM Go6976, a selective protein kinase C inhibitor, blocked the neuroprotective effect of GM1. In contrast to its antiapoptotic effect, GM1 at up to 200 microM did not attenuate cortical neuronal necrosis induced by exposure to the excitotoxins N-methyl-D-aspartate or kainate. Furthermore, GM1 increased the necrosis induced by oxidative stress (addition of Fe(2+) or buthionine sulfoximine). These data suggest that neuroprotective effects of natural gangliosides may preferentially reflect reduction of neuronal apoptosis rather than necrosis, and be mediated through mechanisms involving activation of phosphatidylinositol 3-kinase.