Asiaticoside (AS) derivatives were tested for potential protective effects against A beta-induced cell death. Of the 28 AS derivatives tested, asiatic acid (AA), asiaticoside 6 (AS6), and SM2 showed strong inhibition of A beta-induced death of B103 cells at 1 mu M, The three AS derivatives were further tested for their effects on free radical injury and apoptosis, All three AS derivatives reduced H2O2-induced cell death and lowered intracellular free radical concentration, but AA showed the strongest protection. In contrast, SM2 was the most effective blocker of staurosporine-induced apoptosis, These results suggest that the three AS derivatives block A beta toxicity by acting through different cellular mechanisms. When applied to hippocampal slices, AA, SM2, and AS6 did not alter n-methyl-D-aspartic acid (NMDA) or non-NMDA receptor-mediated synaptic transmission, paired-pulse facilitation or induction of long-term potentiation in the field CA1. These results indicate that the three AS derivatives do not alter physiological properties of the hippocampus at the concentration that blocks A beta-induced cell death, Therefore AS6, AA, and SM2 can be regarded as reasonable candidates for a therapeutic Alzheimer's disease drug that protects neurons from A beta toxicity. J, Neurosci, Res. 58:417-425, 1999, (C) 1999 Wiley-Liss, Inc.