Waldmeier P C, Boulton A A, Cools A R, Kato A C, Tatton W G
Nervous System Research, Novartis Pharma Ltd, Basel, Switzerland.
J Neural Transm Suppl. 2000(60):197-214. doi: 10.1007/978-3-7091-6301-6_13.
(-)-Deprenyl, used for the treatment of Parkinson's disease, was reported to possess neurorescuing/antiapoptotic effects independent of its MAO-B inhibiting properties. It is metabolized to (-)-desmethyldeprenyl, which seems to be the active principle, and further to (-)-amphetamine and (-)-methamphetamine, which antagonize its rescuing effects. These complications may explain the limited neurorescuing potential of (-)-deprenyl observed clinically. CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine), structurally related to (-)-deprenyl, exhibits virtually no MAO-B nor MAO-A inhibiting properties and is not metabolized to amphetamines. It was shown to bind to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme with multiple other functions including an involvement in apoptosis, and shows neurorescuing properties qualitatively similar to, but about 100-fold more potent than those of (-)-deprenyl in several in vitro and in vivo paradigms. In concentrations ranging from 10(-13)-10(-5) M, it rescues partially differentiated PC12 cells from apoptosis induced by trophic withdrawal, cerebellar granule cells from apoptosis induced by cytosine arabinoside, rat embryonic mesencephalic dopaminergic cells from death caused by MPP+, and PAJU human neuroblastoma cells from death caused by rotenone. However, it did not affect apoptosis elicited by a variety of agents in rapidly proliferating cells from thymus or skin or in liver or kidney cells. In vivo, it rescued facial motor neuron cell bodies in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia, and mouse nigral dopaminergic cell bodies from death induced by MPTP, in doses ranging between 0.0003 and 0.1 mg/kg p.o. or s.c., depending on the model. It also partially prevented the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra of 6-OHDA-lesioned rats and improved motor function in these animals. Moreover, it prolonged the life-span of progressive motor neuronopathy (pmn) mice (a model for ALS), preserved their body weight and improved their motor performance. This was accompanied by a decreased loss of motor neurons and motor neuron fibers, and protection of mitochondria. The active concentration- or dose-ranges in the different in vitro and in vivo paradigms were remarkably similar. In several paradigms, bell-shaped dose-response curves were observed, the rescuing effect being lost above about 1 mg/kg, a fact that must be considered in clinical investigations.
（-）-司来吉兰用于治疗帕金森病，据报道其具有神经保护/抗凋亡作用，且与其单胺氧化酶B（MAO-B）抑制特性无关。它代谢为（-）-去甲基司来吉兰，这似乎是其活性成分，还会进一步代谢为（-）-苯丙胺和（-）-甲基苯丙胺，而这两种物质会拮抗其保护作用。这些复杂情况可能解释了临床上观察到的（-）-司来吉兰有限的神经保护潜力。CGP 3466（二苯并[b,f]氧杂环庚三烯-10-基甲基-甲基-丙-2-炔基-胺）在结构上与（-）-司来吉兰相关，几乎不具有MAO-B和MAO-A抑制特性，也不会代谢为苯丙胺类物质。已证明它能与甘油醛-3-磷酸脱氢酶结合，该酶是一种糖酵解酶，具有多种其他功能，包括参与细胞凋亡，并且在几种体外和体内实验模型中显示出与（-）-司来吉兰性质相似但效力约强100倍的神经保护特性。在浓度范围为10^(-13) - 10^(-5) M时，它能使部分分化的PC12细胞免受营养物质剥夺诱导的凋亡，使小脑颗粒细胞免受阿糖胞苷诱导的凋亡，使大鼠胚胎中脑多巴胺能细胞免受1-甲基-4-苯基吡啶离子（MPP+）导致的死亡，以及使PAJU人神经母细胞瘤细胞免受鱼藤酮导致的死亡。然而，它不影响胸腺或皮肤快速增殖细胞、肝细胞或肾细胞中多种因素引发的凋亡。在体内，在口服或皮下给药剂量为0.0003至0.1 mg/kg（取决于模型）时，它能挽救大鼠幼崽轴突切断后面神经运动神经元胞体、短暂缺血/缺氧后大鼠海马CA1神经元以及小鼠黑质多巴胺能细胞胞体免受1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的死亡。它还部分预防了6-羟基多巴胺（6-OHDA）损伤大鼠黑质中酪氨酸羟化酶免疫反应性的丧失，并改善了这些动物的运动功能。此外，它延长了进行性运动神经元病（pmn）小鼠（肌萎缩侧索硬化症模型）的寿命，维持了它们的体重并改善了运动表现。这伴随着运动神经元和运动神经元纤维损失的减少以及线粒体的保护。在不同的体外和体内实验模型中，活性浓度或剂量范围非常相似。在几个实验模型中观察到钟形剂量反应曲线，在约1 mg/kg以上保护作用消失，这一事实在临床研究中必须予以考虑。
