Additive effects of caspase inhibitor and lazaroid on the survival of transplanted rat and human embryonic dopamine neurons

Major practical constraints on neural grafting in Parkinson's disease are t he shortage of human donor tissue and the great loss of dopamine neurons du ring the grafting procedure. The vast majority of implanted embryonic dopam ine neurons are believed to die within a few days of transplantation surger y, at least in part through apoptosis. We have previously found that surviv al of nigral grafts in rodents can be significantly augmented by pretreatme nt with the caspase inhibitor Ac-YVAD-cmk or by lazaroids (lipid peroxidati on inhibitors). We now report that pretreatment with the caspase inhibitor Ac-DEVD-cmk, but not z-VAD-fmk, results in a significantly improved surviva l of transplanted dopamine neurons of similar magnitude to that achieved in this study using Ac-YVAD-cmk (both 220-230% of control). In addition, we f ound that treatment of the graft tissue with tirilazad mesylate (a lazaroid allowed for clinical use) almost doubled the survival of grafted dopamine neurons. When Ac-YVAD-cmk and tirilazad mesylate treatments were combined, the number of surviving dopamine neurons increased significantly further to 280% of control. Importantly, the same combination of neuroprotectants enh anced the survival of human dopamine neurons xenotransplanted to immunosupp ressed rats (to 240% of control). In conclusion, these results suggest that combining treatments that counteract oxidative stress and caspase activati on is a valuable strategy to enhance nigral graft survival that should be c onsidered for clinical application. (C) 2000 Academic Press.