Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline

被引:129
作者
Bar Am, O
Amit, T
Youdim, MBH
机构
[1] Technion Israel Inst Technol, Fac Med, Eve Topf & US Natl Parkinson Fdn, Ctr Excellence Neurodegenerat Dis Res, IL-31096 Haifa, Israel
[2] Technion Israel Inst Technol, Fac Med, Dept Pharmacol, IL-31096 Haifa, Israel
关键词
Parkinson's disease; neuroprotection; neurotoxicity rasagiline; selegiline; aminoindan; L-methamphetamine; PKC-MAP kinase pathway;
D O I
10.1016/j.neulet.2003.10.067
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 muM) or selegiline (1 muM) is neuroprotective and anti-apoptotic as determined by Eliza and MTT tests. However, while aminoindan (1 muM), 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 muM), 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 muM), 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. (C) 2003 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:169 / 172
页数:4
相关论文
共 20 条
[1]   Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells [J].
Abu-Raya, S ;
Tabakman, R ;
Blaugrund, E ;
Trembovler, V ;
Lazarovici, P .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2002, 434 (03) :109-116
[2]   Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan [J].
Akao, Y ;
Maruyama, W ;
Shimizu, S ;
Yi, H ;
Nakagawa, Y ;
Shamoto-Nagai, M ;
Youdim, MBH ;
Tsujimoto, Y ;
Naoi, M .
JOURNAL OF NEUROCHEMISTRY, 2002, 82 (04) :913-923
[3]  
BIRKMAYER W, 1977, LANCET, V1, P439
[4]  
Finberg J P, 1999, Adv Neurol, V80, P495
[5]   Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours [J].
Finberg, JPM ;
Youdim, MBH .
NEUROPHARMACOLOGY, 2002, 43 (07) :1110-1118
[6]   Attenuation of methamphetamine induced dopaminergic neurotoxicity by flupirtine: microdialysis study on dopamine release and free radical generation [J].
Gassen, M ;
Lamensdorf, I ;
Armony, T ;
Finberg, JPM ;
Youdim, MBH .
JOURNAL OF NEURAL TRANSMISSION, 2003, 110 (02) :171-182
[7]   Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor [J].
Maruyama, W ;
Weinstock, M ;
Youdim, MBH ;
Nagai, M ;
Naoi, M .
NEUROSCIENCE LETTERS, 2003, 341 (03) :233-236
[8]  
Maruyama W, 2000, ADV RES NEURODEGENER, V8, P171
[9]   (-)-DEPRENYL ALTERS THE SURVIVAL OF ADULT MURINE FACIAL MOTONEURONS AFTER AXOTOMY - INCREASES IN VULNERABLE C57BL STRAIN BUT DECREASES IN MOTOR-NEURON DEGENERATION MUTANTS [J].
OH, C ;
MURRAY, B ;
BHATTACHARYA, N ;
HOLLAND, D ;
TATTON, WG .
JOURNAL OF NEUROSCIENCE RESEARCH, 1994, 38 (01) :64-74
[10]   Protection with metabotropic glutamate 1 receptor antagonists in models of ischemic neuronal death: time-course and mechanisms [J].
Pellegrini-Giampietro, DE ;
Peruginelli, F ;
Meli, E ;
Cozzi, A ;
Albani-Torregrossa, S ;
Pellicciari, R ;
Moroni, F .
NEUROPHARMACOLOGY, 1999, 38 (10) :1607-1619