Mandel Silvia, Weinreb Orly, Amit Tamar, Youdim Moussa B H
Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Research, Israel.
Brain Res Brain Res Rev. 2005 Apr;48(2):379-87. doi: 10.1016/j.brainresrev.2004.12.027.
The mitochondria are directly involved in cell survival and death. Drugs that protect mitochondria viability and prevent apoptotic cascade mechanisms involved in mitochondrial permeability transition pore (MPTp) will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor, anti-Parkinson drug. Unlike selegiline, rasagiline is not derived from amphetamine, is not metabolized to neurotoxic l-methamphetamine derivative, nor does it have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to L-dopa for patients with early and late Parkinson's disease (PD), and adverse events do not occur with greater frequency in subjects receiving rasagiline than those on placebo. Controlled studies indicate that it might have a disease-modifying effect in PD that may be related to neuroprotection. Its S-isomer, TVP1022, is a relatively inactive MAO inhibitor. However, both drugs have similar neuroprotective activities in neuronal cell cultures in response to various neurotoxins and in vivo (global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a pre-requisite for neuroprotection. Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha) by PKC and MAP kinase-dependent activation of alpha-secretase. The neuroprotective activity of propargylamine has led us to develop novel bifunctional neuroprotective iron-chelating MAO-inhibiting drugs possessing propargyl moiety for the treatment of other neurodegenerative diseases.
线粒体直接参与细胞的存活与死亡。保护线粒体活力并防止与线粒体通透性转换孔（MPTp）相关的凋亡级联机制的药物将具有细胞保护作用。雷沙吉兰（N-炔丙基-1R-氨基茚）是一种新型、高效的不可逆单胺氧化酶（MAO）B抑制剂，用于治疗帕金森病。与司来吉兰不同，雷沙吉兰并非源自苯丙胺，不会代谢为具有神经毒性的L-甲基苯丙胺衍生物，也没有拟交感神经活性。雷沙吉兰作为单一疗法或左旋多巴的辅助药物，对早、晚期帕金森病（PD）患者均有效，且接受雷沙吉兰治疗的患者出现不良事件的频率并不高于接受安慰剂治疗的患者。对照研究表明，它可能对帕金森病具有疾病修饰作用，这可能与神经保护有关。其S-异构体TVP1022是一种相对无活性的MAO抑制剂。然而，这两种药物在神经元细胞培养物中针对各种神经毒素以及在体内（全脑缺血、神经创伤、头部损伤、缺氧等）均具有相似的神经保护活性，这表明MAO抑制并非神经保护的先决条件。结构活性研究表明，神经保护活性与雷沙吉兰的炔丙基部分有关，该部分通过激活Bcl-2和蛋白激酶C（PKC）以及下调促凋亡的FAS和Bax来保护线粒体活力和MPTp。雷沙吉兰及其衍生物还通过PKC和丝裂原活化蛋白激酶（MAP激酶）依赖性激活α-分泌酶，将淀粉样前体蛋白（APP）加工成具有神经保护和神经营养作用的可溶性APPα（sAPPα）。炔丙胺的神经保护活性促使我们开发具有炔丙基部分的新型双功能神经保护铁螯合MAO抑制药物，用于治疗其他神经退行性疾病。
