Indolylazine Derivative Induces Chaperone Expression in Aged Neural Cells and Prevents the Progression of Alzheimer's Disease.
Vladimir F LazarevElizaveta A DutyshevaElena R MikhaylovaMaria A TrestsovaIrina A UtepovaOleg N ChupakhinBoris A MargulisIrina V GuzhovaPublished in: Molecules (Basel, Switzerland) (2022)
The risk of progression of most sporadic neurodegenerative diseases, including Alzheimer's disease, increases with age. Traditionally, this is associated with a decrease in the efficiency of cell protection systems, in particular, molecular chaperones. Thus, the development of small molecules able to induce the synthesis of chaperones is a promising therapeutic approach to prevent neural diseases associated with ageing. Here, we describe a new compound IA-50 , belonging to the class of indolylazines and featured by a low size of topological polar surface area, the property related to substances with potentially high membrane-penetrating activity. We also estimated the absorption, distribution, metabolism and excretion characteristics of IA-50 and found the substance to fit the effective drug criteria. The new compound was found to induce the synthesis and accumulation of Hsp70 in normal and aged neurons and in the hippocampi of young and old mice. The transgenic model of Alzheimer's disease, based on 5xFAD mice, confirmed that the injection of IA-50 prevented the formation of β-amyloid aggregates, loss of hippocampal neurons and the development of memory impairment. These data indicate that this novel substance may induce the expression of chaperones in neural cells and brain tissues, suggesting its possible application in the therapy of ageing-associated disorders.
Keyphrases
- heat shock
- induced apoptosis
- poor prognosis
- cognitive decline
- cell cycle arrest
- spinal cord
- heat shock protein
- endoplasmic reticulum stress
- cell therapy
- oxidative stress
- heat stress
- high fat diet induced
- drinking water
- bone marrow
- big data
- signaling pathway
- artificial intelligence
- mouse model
- cell death
- white matter
- spinal cord injury
- wild type
- single molecule
- skeletal muscle