Lazaroid treatment prevents death of cultured rat embryonic mesencephalic neurons following glutathione depletion.
Reactive oxygen species are believed to play a crucial role in situations where dopamine neurons die, such as in Parkinson's disease or during intracerebral transplantation of embryonic mesencephalic tissue. The present study was designed to address the question whether, and to what extent, the glutathione redox system is important for the viability of rat embryonic dopamine neurons in vitro. Furthermore, we studied whether the lazaroid U-83836E, a 2-methylaminochroman that inhibits lipid peroxidation, affects the survival of cultured mesencephalic neurons subjected to experimentally induced glutathione depletion. Glutathione depletion was achieved by exposing dissociated mesencephalic cell cultures to L-buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, at four different concentrations (1, 10,100, and 1,000 microM). Dopamine neuron survival was significantly reduced by 65-94% in a concentration-dependent manner by 10-1,000 microM BSO. The neurotoxic effects of BSO were almost completely prevented by supplementing the culture medium with 0.3 microM U-83836E. As assessed by HPLC analysis, BSO treatment was associated with a marked reduction of cellular glutathione content, and this depletion was not altered by the presence of U-83836E. We conclude that in the present insult model of severe glutathione depletion, the lazaroid can afford efficient neuroprotection that does not seem to be mediated by a direct interaction with BSO or glutathione, but rather via an independent pathway.
Grasbon-Frodl
E M
EM
Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund, Sweden.
Andersson
A
A
Brundin
P
P
D000704:Analysis of Variance; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002839:Chromans; D016166:Free Radical Scavengers; D009498:Neurotoxins; D010879:Piperazines; C066382:U 78517F; D019328:Buthionine Sulfoximine; D005978:Glutathione; D004298:Dopamine