The Wld(s) mouse mutant demonstrates a remarkable phenotype of delayed axonal and synaptic degeneration after nerve lesion. In this study, the authors tested the hypothesis that expression of Wld protein is neuroprotective in an in vivo mouse model of global cerebral ischemia. This model is associated with selective neuronal degeneration in specific brain regions such as the caudate nucleus and CA2 hippocampal pyramidal cell layer. The extent of neuronal damage was quantified in Wld(s) compared to wild-type mice after an identical episode of global cerebral ischemia. The results demonstrated a significant and marked reduction in the extent of neuronal damage in Wld(s) as compared to wild-type C57Bl/6 mice. In the caudate nucleus, Wld expression significantly reduced the percentage of ischemic neuronal damage after global ischemia (Wld(s), 27.7 +/- 16.8%; wild-type mice, 58.7 +/- 32.3%; P = 0.036). Similarly, in the CA2 pyramidal cell layer, there was a significant reduction of neuronal damage in the Wld(s) mice as compared to wild-type mice after ischemia (Wld(s), 17.7 +/- 23.0%; wild-type mice, 41.9 +/- 28.0%; P < 0.023). Thus, these results clearly demonstrate that the Wld gene confers substantial neuroprotection after cerebral ischemia, and suggest a new role to that previously described for Wld(s).