Tempol attenuates cocaine-induced death of PC12 cells through decreased oxidative damage.
The association between cocaine administration and induction of oxidative stress in different brain regions suggests that oxidative damage is an important factor participating in cocaine disruption of normal central nervous system functions. In order to deal with this topic, brain penetrating exogenous antioxidants were suggested as a tool to prevent cocaine-induced oxidative damage and behavioral changes. Lately, we have shown that Tempol, a stable nitroxide radical reduced oxidative damage and attenuated the development and expression of cocaine psychomotor sensitization. To examine whether nitroxides, represented by Tempol, can exhibit protective effects against cocaine-induced cell death and to elucidate the molecular mechanism of cocaine-induced oxidative damage, we used the well established PC12 cell line model. The results showed that (1) cocaine induced cell death in a dose-dependent manner (2) and that it was reduced significantly by the stable nitroxide radical Tempol. Furthermore, (3) Tempol significantly inhibited oxidative damage induced by cocaine as reflected by mitochondrial superoxide radical and peroxide enhancement. Finally, (4) Tempol restored the total scavenging capacity which was reduced by cocaine in PC12 cells. Cumulatively, these results suggest that nitroxides such as Tempol can attenuate oxidative damage and cell death induced by cocaine and that PC12 cells can be used as an in vitro model to further investigate the precise molecular mechanism of these compounds.
Numa
Ran
R
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Baron
Meggie
M
Kohen
Ron
R
Yaka
Rami
R
D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D003042:Cocaine / Q000633:toxicity*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D051381:Rats; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D003497:Cyclic N-Oxides; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D013113:Spin Labels; D013481:Superoxides; D013482:Superoxide Dismutase; D003042:Cocaine; C001803:tempol