Comparison between survival of lazaroid-treated embryonic nigral neurons in cell suspensions, cultures and transplants.
Death of transplanted dopaminergic neurons is induced both during preparation of donor tissue and after intrastriatal grafting. Oxidative stress is thought to be partly responsible for this cell death. In the present study we compared the effects of three lipid peroxidation inhibitors, the lazaroids Tirilazad mesylate, U-83836E and U-101033, on survival of embryonic mesencephalic neurons in different paradigms. The lazaroids were equally potent in preventing serum deprivation-induced death of cultured dopaminergic neurons. In a second set of experiments, mesencephalic suspensions were pretreated with lazaroids and cell survival was analyzed immediately after dissociation, after 2 or 24 h in culture or after intrastriatal transplantation. Lazaroid pretreatment failed to protect mesencephalic neurons in the in vitro paradigms and U-101033E did not protect grafted dopaminergic neurons in contrast to the neuroprotective effects previously reported for U-83836E and Tirilazad. Pretreatment with the iron chelator deferoxamine mesylate did not protect cultured or grafted dopaminergic neurons, nor did it improve neuronal survival in the serum deprivation model. U-83836E and U-101033E, but not Tirilazad, prevented cell death induced by the pro-oxidant tert-butyl hydroperoxide in suspensions. In a final experiment, we found that systemic treatment of the graft recipient rat with Tirilazad mesylate (before and during the first 3 days after grafting) improved survival of transplanted dopaminergic neurons to 180% of control values. Our results show that systemic treatment with a lipid peroxidation inhibitor for 3 days can promote graft survival, but also highlights the poor correlation between neuroprotective effect of pharmacological compounds in vitro and in grafts.
Karlsson
Jenny
J
Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, BMC A10, S-221 84, Lund, Sweden.
Emgård
Mia
M
Brundin
Patrik
P
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004622:Embryo, Mammalian; D005227:Fatty Acids / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects* / Q000502:physiology; D008636:Mesencephalon / Q000187:drug effects / Q000637:transplantation; D009474:Neurons / Q000187:drug effects* / Q000637:transplantation*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000637:transplantation*
D000975:Antioxidants; D002839:Chromans; D005227:Fatty Acids; D010879:Piperazines; D011743:Pyrimidines; D011759:Pyrrolidines; C101923:U 101033E; C013584:lipid peroxidation inhibitor; C066382:U 78517F