Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline.
The anti-Parkinson selective irreversible monoamine oxidase B inhibitor drugs, rasagiline and selegiline, have been shown to possess neuroprotective activities in cell culture and in vivo models. While rasagiline is metabolized to its major metabolite aminoindan, selegiline gives rise to L-methamphetamine. Cultured PC-12 cells in absence of serum and nerve growth factor (NGF) die by an apoptotic process. Pretreatment of PC12 cells in absence of serum and NGF for 24 h with either rasagiline (1 microM) or selegiline (1 microM) is neuroprotective and anti-apoptotic as determined by ELISA and MTT tests. However, while aminoindan (1 microM), the major metabolite of rasagiline does not interfere with the neuroprotective activities of rasagiline or selegiline in PC-12 cells deprived of serum and NGF, the major metabolite of selegiline, L-methamphetamine (1 microM), inhibits them. In contrast to L-methamphetamine, aminoindan is itself is neuroprotective in this system. Recently it has been demonstrated that rasagiline directly activates PKC-MAP kinase pathway by a concentration and time dependent phosphorylation of p42 and p44 MAP kinase. In the present studies the neuroprotective activity of rasagiline is blocked by ERK inhibitor, PD98059 (20 microM), suggesting the involvement of PKC-MAP kinase pathway in the neuroprotection. These findings may have implication for the possible disease modifying action of rasagiline in treatment of Parkinson's disease.
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Orit
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Eve Topf and US National Parkinson Foundation Center of Excellence for Neurodegenerative Diseases Research, Technion-Faculty of Medicine, Efron St PO Box 9697, Haifa 31096, Israel.
Amit
Tamar
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Youdim
Moussa B H
MB
D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D007189:Indans / Q000378:metabolism / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D012642:Selegiline / Q000378:metabolism / Q000633:toxicity*
D000978:Antiparkinson Agents; D007189:Indans; D018696:Neuroprotective Agents; C031967:rasagiline; D012642:Selegiline