Youdim Moussa B H, Maruyama Wakako, Naoi Makato
Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Rappaport Faculty of Medicine, Haifa, Israel.
Drugs Today (Barc). 2005 Jun;41(6):369-91. doi: 10.1358/dot.2005.41.6.893613.
Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent, irreversible monoamine oxidase (MAO)-B inhibitor designed for use as an antiparkinsonian drug. Unlike selegiline, rasagiline is not derived from amphetamine or metabolized to neurotoxic l-methamphetamine derivative, and it does not have sympathomimetic activity. Moreover, at selective MAO-B inhibitory dosage, it does not induce a "cheese reaction." Rasagiline is effective as monotherapy or as an adjunct to L-dopa for patients with early and late Parkinson's disease. Adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Its S-isomer, TVP1022, is more than a thousand times less potent as an MAO inhibitor. However, both drugs have neuroprotective activities in neuronal cell cultures in response to various neurotoxins, as well as in vivo (e.g., in response to global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a prerequisite for neuroprotection. The neuroprotective activity of these drugs has been demonstrated to be associated with the propargylamine moiety, which protects mitochondrial viability and mitochondrial permeability transition pore by activating Bcl-2 and downregulating the Bax family of proteins. Rasagiline processes amyloid precursor protein (APP) into the neuroprotective-neurotrophic soluble APPalpha (sAPPalpha) by protein kinase C- and mitogen-activated protein kinase-dependent activation of alpha-secretase, and increases nerve growth factor, glial cell- derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) expression and proteins. Thus, rasagiline may induce neuroprotection, neuroplasticity and long-term potentiation. Rasagiline has therefore been chosen by the National Institutes of Health (NIH) to study its neuroprotective effects in neurodegenerative diseases. Long-term studies are required to evaluate the drug's disease-modifying prospects in Parkinson's and Alzheimer's diseases.
雷沙吉兰（N-炔丙基-1R-氨基茚）是一种新型、高效、不可逆的单胺氧化酶（MAO）-B抑制剂，被设计用作抗帕金森病药物。与司来吉兰不同，雷沙吉兰并非源自苯丙胺，也不会代谢为具有神经毒性的L-甲基苯丙胺衍生物，且不具有拟交感神经活性。此外，在选择性MAO-B抑制剂量下，它不会引发“奶酪反应”。雷沙吉兰作为单一疗法或左旋多巴的辅助药物，对早期和晚期帕金森病患者均有效。接受雷沙吉兰治疗的受试者中不良事件的发生频率并不高于接受安慰剂治疗的受试者。其S-异构体TVP1022作为MAO抑制剂的效力比雷沙吉兰低一千多倍。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（例如，针对全脑缺血、神经创伤、头部损伤、缺氧等）均具有神经保护活性，这表明MAO抑制并非神经保护的先决条件。已证明这些药物的神经保护活性与炔丙胺部分有关，该部分通过激活Bcl-2和下调Bax蛋白家族来保护线粒体活力和线粒体通透性转换孔。雷沙吉兰通过蛋白激酶C和丝裂原活化蛋白激酶依赖性激活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），并增加神经生长因子、胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）的表达及蛋白水平。因此，雷沙吉兰可能诱导神经保护、神经可塑性和长时程增强。因此，美国国立卫生研究院（NIH）选择雷沙吉兰来研究其在神经退行性疾病中的神经保护作用。需要进行长期研究以评估该药物在帕金森病和阿尔茨海默病中改善病情的前景。
