Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells.
Selegiline and rasagiline are selective and irreversible monoamine oxidase-B inhibitors that exert neuroprotective effects in various preclinical models. The aim of the present study was to examine the effect of selegiline and its major metabolite, L-methamphetamine in comparison to rasagiline and its major metabolite, 1-R-aminoindan on oxygen-glucose deprivation induced cell death in nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cells. Our results show that selegiline reduces oxygen-glucose deprivation induced cell death by 30%. When the cultures were treated with rasagiline at similar concentrations, cell death induced by oxygen-glucose deprivation was reduced by 45-55%. L-methamphetamine, a major selegiline metabolite, but not 1-R-aminoindan, the major rasagiline metabolite, enhanced oxygen-glucose deprivation-induced cell death by 70%. Under normoxic conditions, both metabolites lack neurotoxicity. Concomitant exposure of the cultures under oxygen-glucose deprivation, to a combination of either selegiline and L-methamphetamine or rasagiline and 1-R-aminoindan, indicated that L-methamphetamine, but not 1-R-aminoindan, blocked the neuroprotective effect of the parental drug. These results suggest there may be a neuroprotective advantage of rasagiline over selegiline.
Abu-Raya
Saleh
S
Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.
Tabakman
Rinat
R
Blaugrund
Eran
E
Trembovler
Victoria
V
Lazarovici
Philip
P
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007511:Ischemia / Q000201:enzymology* / Q000473:pathology*; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D016716:PC12 Cells / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D051381:Rats
D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D008995:Monoamine Oxidase