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 the shortage of human donor tissue and the great loss of dopamine neurons during the grafting procedure. The vast majority of implanted embryonic dopamine neurons are believed to die within a few days of transplantation surgery, at least in part through apoptosis. We have previously found that survival of nigral grafts in rodents can be significantly augmented by pretreatment with the caspase inhibitor Ac-YVAD-cmk or by lazaroids (lipid peroxidation inhibitors). We now report that pretreatment with the caspase inhibitor Ac-DEVD-cmk, but not z-VAD-fmk, results in a significantly improved survival 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 found 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 enhanced the survival of human dopamine neurons xenotransplanted to immunosuppressed rats (to 240% of control). In conclusion, these results suggest that combining treatments that counteract oxidative stress and caspase activation is a valuable strategy to enhance nigral graft survival that should be considered for clinical application.
Hansson
O
O
Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund, Sweden.
Castilho
R F
RF
Kaminski Schierle
G S
GS
Karlsson
J
J
Nicotera
P
P
Leist
M
M
Brundin
P
P
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D061945:Caspase Inhibitors; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000637:transplantation; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D018696:Neuroprotective Agents / Q000494:pharmacology; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000975:Antioxidants; D061945:Caspase Inhibitors; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D018696:Neuroprotective Agents; D011281:Pregnatrienes; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; C053355:tirilazad