中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (1): 30-35.doi: 10.4103/1673-5374.262679

• 综述:退行性病与再生 • 上一篇    下一篇

ASS234亮点:阿尔茨海默病治疗的新型和有前景的治疗剂

  

  • 出版日期:2020-01-15 发布日期:2020-05-14

Highlights of ASS234: a novel and promising therapeutic agent for Alzheimer’s disease therapy

Alejandro Romero1, *, José Marco-Contelles2, Eva Ramos1, *   

  1. 1 Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain
    2 Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry (CSIC) Madrid, Spain
  • Online:2020-01-15 Published:2020-05-14
  • Contact: Eva Ramos, PhD,eva.ramos@ucm.es;Alejandro Romero, PhD,manarome@ucm.es.

摘要: orcid: 0000-0001-5483-4973 (Alejandro Romero)
         0000-0001-5791-0687 (Eva Ramos)
         0000-0003-0690-0328 (José Marco-Contelles)

Abstract: There is no effective treatment to face Alzheimer’s disease complexity. Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression. In this context, N-((5-(3-(1-benzylpiperidin-4-yl) propoxy)-1- methyl-1H-indol-2-yl)methyl)-N-methylprop- 2-yn-1-amine (ASS234) has been tested achieving promising results. ASS234 has demonstrated to cross the blood-brain barrier in vivo, and a good in silico safety profile being less toxic than donepezil. Besides, ASS234 reversibly inhibits human acetyl- and butyryl-cholinesterase, and irreversibly inhibits human monoamine oxidase A and B. Moreover, this multitarget molecule has antioxidant and neuroprotective properties, and inhibits Αβ1–42 and Αβ1–40 self-aggregation. Inquiring about the mechanism of action, several signaling pathways related to Alzheimer’s disease had been explored showing that ASS234 induces the wingless-type MMTV integration site (Wnt) family and several members of the heat shock proteins family and moreover counteracts neuroinflammatory and oxidative stress-related genes promoting the induction of several key antioxidant genes. Finally, in vivo experiments with ASS234 in C57BL/6J mice displayed its ability to reduce amyloid plaque burden and gliosis in the cortex and hippocampus, ameliorating scopolamine- induced learning deficits. Here we gather the information regarding ASS234 evaluated so far, showing its ability to face different targets, necessary to counteract a neurodegenerative disease as complex as the Alzheimer’s disease.

Key words: AChE, BuChE, gene expression, heat shock proteins, inflammation, in silico toxicology, MAO A/B, neuroprotection, oxidative stress, Wnt signaling