Department of Pharmacology, Rappaport Family Research Institute, Haifa, Israel.
Curr Drug Targets. 2012 Apr;13(4):483-94. doi: 10.2174/138945012799499794.
Ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] is a dual acetylcholine-butyrylcholineesterase and brain selective monoamine oxidase (MAO)-A and -B inhibitor in vivo (with little or no MAO inhibitory effect in the liver and small intestine), intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression (presently in a Phase IIb clinical study). This suggests that the drug should not cause a significant potentiation of the cardiovascular response to tyramine, thereby making it a potentially safer antidepressant than other irreversible MAO-A inhibitors. Ladostigil was shown to antagonize scopolamine-induced impairment in spatial memory, indicating that it can cause significant increases in rat brain cholinergic activity. Furthermore, ladostigil prevented gliosis and oxidative-nitrative stress and reduced the deficits in episodic and spatial memory induced by intracerebroventricular injection of streptozotocin in rats. Ladostigil was demonstrated to possess potent anti-apoptotic and neuroprotective activities in vitro and in various neurodegenerative rat models, (e.g. hippocampal damage induced by global ischemia in gerbils and cerebral oedema induced in mice by closed head injury). These neuroprotective activities involve regulation of amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase signaling pathways; inhibition of neuronal death markers; prevention of the fall in mitochondrial membrane potential and upregulation of neurotrophic factors and antioxidative activity. Recent findings demonstrated that the major metabolite of ladostigil, hydroxy-1-(R)-aminoindan has also a neuroprotective activity and thus, may contribute to the overt activity of its parent compound. This review will discuss the scientific evidence for the therapeutic potential use of ladostigil in Alzheimer's and Lewy Body diseases and the molecular signaling pathways that are considered to be involved in the biological activities of the drug.
拉多替吉 [(N-丙炔基-(3R)氨基茚满-5-基)-乙基甲基氨基甲酸酯] 是一种体内双重乙酰胆碱-丁酰胆碱酯酶和脑选择性单胺氧化酶（MAO）-A 和 -B 抑制剂（在肝脏和小肠中几乎没有或没有 MAO 抑制作用），旨在治疗伴有锥体外系疾病和抑郁症的痴呆症（目前正在进行 IIb 期临床研究）。这表明该药物不应引起对酪胺心血管反应的显著增强，从而使其成为一种比其他不可逆 MAO-A 抑制剂更安全的抗抑郁药。拉多替吉已被证明可拮抗东莨菪碱引起的空间记忆损伤，表明它可引起大鼠脑胆碱能活性的显著增加。此外，拉多替吉可预防神经胶质增生和氧化硝化应激，并减少脑室注射链脲佐菌素引起的大鼠情景和空间记忆缺陷。拉多替吉已被证明在体外和各种神经退行性大鼠模型中具有强大的抗凋亡和神经保护活性，（例如沙鼠全脑缺血引起的海马损伤和小鼠闭合性颅脑损伤引起的脑水肿）。这些神经保护活性涉及淀粉样前体蛋白处理的调节；蛋白激酶 C 和有丝分裂原激活蛋白激酶信号通路的激活；神经元死亡标志物的抑制；防止线粒体膜电位下降和神经营养因子和抗氧化活性的上调。最近的研究结果表明，拉多替吉的主要代谢物羟基-1-(R)-氨基茚满也具有神经保护活性，因此可能有助于其母体化合物的明显活性。这篇综述将讨论拉多替吉在阿尔茨海默病和路易体病中的治疗潜力的科学证据，以及被认为参与药物生物学活性的分子信号通路。
