Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells
Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells
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DOI：
10.1016/s0014-2999(01)01548-5
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发表时间：
2002-01-11
影响因子：
5
通讯作者：
Lazarovici, P
中科院分区：
文献类型：
--
作者：
Abu-Raya, S;Tabakman, R;Lazarovici, P
司来吉兰和雷沙吉兰是选择性和不可逆的单胺氧化酶-B抑制剂，在各种临床前模型中发挥神经保护作用。本研究的目的是检查司来吉兰及其主要代谢产物L-甲基苯丙胺与雷沙吉兰及其主要代谢产物1-R-氨基茚满相比对神经生长因子（NGF）分化的嗜铬细胞瘤（PC 12）细胞中氧-葡萄糖剥夺诱导的细胞死亡的影响。我们的研究结果表明，司来吉兰减少30%的氧-葡萄糖剥夺诱导的细胞死亡。当用相似浓度的雷沙吉兰处理培养物时，由氧-葡萄糖剥夺诱导的细胞死亡减少了45- 55%。司来吉兰的主要代谢产物L-甲基苯丙胺，而不是雷沙吉兰的主要代谢产物1-R-氨基茚满，使氧-葡萄糖剥夺诱导的细胞死亡增加70%。在非中毒条件下，两种代谢物均无神经毒性。伴随暴露的培养物下的氧-葡萄糖剥夺，无论是司来吉兰和L-甲基苯丙胺或雷沙吉兰和1-R-氨基茚满的组合，表明L-甲基苯丙胺，但不是1-R-氨基茚满，阻断了母体药物的神经保护作用。这些结果表明雷沙吉兰可能比司来吉兰具有神经保护优势。(C)2002 Elsevier Science B. V.保留所有权利。
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 nonnoxic 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. (C) 2002 Elsevier Science B.V. All rights reserved.