We investigated the neuroprotective effect of echinacoside, one of the phenylethanoids isolated from the stems of Cistanches salsa, a Chinese herbal medicine, on tumor necrosis factor-alpha (TNFa)-induced apoptosis in human neuroblastoma (SHSY5Y) cells. Treatment of cultured SHSY5Y cells with TNFa 100 ng ml 1 for 36 h stimulated apoptosis, as demonstrated by typical morphological changes, cell viability, DNA laddering, annexin-V binding, intracellular reactive oxygen species, mitochondrial membrane potential and caspase-3 activity. However, simultaneous treatment with echinacoside (1, 10 or 100 Ag ml 1) attenuated the TNFa-mediated apoptosis. The antiapoptotic action of echinacoside was partially dependent on antioxidative stress effects, maintenance of mitochondria function, inhibition of caspase-3 activity and was also associated with increasing the expression of the antiapoptotic protein Bcl2. Thus, echinacoside has the neuroprotective capacity to antagonize TNFa-induced apoptosis in SHSY5Y cells and may be useful in treating some neurodegenerative diseases. D 2004 Elsevier B.V. All rights reserved.