Background. The nitrone compound NXY-059 (disodium 2,4-sulphophenyl-N-tert-butylnitrone) is a free radical trapping agent that is neuroprotective in both rodent and primate models of acute ischaemic stroke (see Green and Ashwood 2005). However, evidence for cytoproprotective activity of nitrones in vitro is sparse. We have therefore investigated whether NXY-059 is cytoprotective in an in vitro preparation, using a neuron-like cell culture model to examine free radical-induced cell damage. Damage was produced by addition of the free radical generating agent sodium nitroprusside (SNP) and we examined the effect of both a cocktail of known antioxidant compounds and NXY-059 on SNP-induced cell death. Methods. Cells of a murine neuroblastoma-derived cell-line (N1E-115) were exposed to sodium nitroprusside (SNP). Cell death was assessed at 24 h by use of the MTT assay of mitochondrial complex II activity and also by microscopic examination of nuclear morphology using Hoechst 33342 chromatin stain to identify apoptotic cells. Results. SNP (10 -1000 μM ) produced concentration-dependent cell death as determined by the MTT assay (EC50 ~ 100 μM at 24 h). A cocktail of known anti-oxidant agents (ascorbate, reduced glutathione and dithiothreitol, all at 100 μM) produced significant protection (P<0.05) against cell death induced by SNP (100 μM), assessed by both the MTT assay (65% reduction in damage) and nuclear morphology counting (100% reduction). In contrast, NXY-059 at a concentration (300 μM) approximately two-fold higher than the plasma concentration required to produce neuroprotection in vivo (Sydserff et al, 2002) was without effect on SNP-induced cytotoxicity. NXY-059 (300 μM) was also without effect on cell death mediated by a related free radical stimulus (100 μM H2O2; 24 h). Conclusion. These results suggest that NXY-059 may not act to protect neurones in the brain following an ischaemic insult and complements recent data suggesting that rather the drug may act to protect the brain endothelium (Culot et al 2006). This proposal supports the concept of neuroprotection by an action at the neurovascular unit (del Zoppo 2006).