Weinreb Orly, Amit Tamar, Bar-Am Orit, Yogev-Falach Merav, Youdim Moussa B H
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, 31096, Israel.
Front Biosci. 2008 May 1;13:5131-7. doi: 10.2741/3069.
The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the multimodal drug, ladostigil (TV3326) ((N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase -A and -B and cholinesterase inhibitory activities in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy Body disease. Preclinical studies show that ladostigil has antidepressant and anti-AD activities and the clinical development is planned for these dementias. In this review, we discuss the multimodal effects of ladostigil in terms of neuroprotective molecular mechanism in vivo and in vitro, which include the amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase pathways; regulation of the Bcl-2 family members; inhibition of cell death markers and up-regulation of neurotrophic factors. Altogether, these scientific findings make ladostigil a potentially valuable drug for the treatment of AD.
最近的治疗方法是设计具有多种药理特性并作用于多个靶点的候选药物，这推动了多模式药物雷多司替（TV3326）（（N-炔丙基-（3R）氨基茚满-5-基）-乙基甲基氨基甲酸酯）的开发。雷多司替在单个分子中结合了神经保护作用以及单胺氧化酶-A和-B及胆碱酯酶抑制活性，作为治疗阿尔茨海默病（AD）和路易体病的潜在药物。临床前研究表明，雷多司替具有抗抑郁和抗AD活性，并且计划针对这些痴呆症进行临床开发。在本综述中，我们从体内和体外神经保护分子机制方面讨论了雷多司替的多模式作用，其中包括淀粉样前体蛋白加工；蛋白激酶C和丝裂原活化蛋白激酶途径的激活；Bcl-2家族成员的调节；细胞死亡标志物的抑制和神经营养因子的上调。总之，这些科学发现使雷多司替成为治疗AD的潜在有价值的药物。
