Rational design, cognition and neuropathology evaluation of QTC-4-MeOBnE in a streptozotocin-induced mouse model of sporadic Alzheimer’s disease

• Published in: Scientific reports 2019-05, Vol.9 (1), p.7276, Article 7276
• Main Authors: Fronza, Mariana G., Baldinotti, Rodolfo, Martins, Maria Clara, Goldani, Bruna, Dalberto, Bianca Thaís, Kremer, Frederico Schmitt, Begnini, Karine, Pinto, Luciano da Silva, Lenardão, Eder João, Seixas, Fabiana K., Collares, Tiago, Alves, Diego, Savegnago, Lucielli
• Format: Article
• Language: English
• Subjects: 119/118; 38/77; 631/154/309/436; 631/92/436; 64/60; Acetylcholinesterase; Alzheimer Disease - chemically induced; Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Cholinergic transmission; Cognition - drug effects; Cognitive ability; Disease Models, Animal; Glycogen; Glycogen synthase kinase 3; Humanities and Social Sciences; Kinases; Lipid peroxidation; Male; Maze Learning - drug effects; Memory Disorders - chemically induced; Memory Disorders - drug therapy; Mice; Molecular Docking Simulation; multidisciplinary; Neuroprotective Agents - therapeutic use; Oxidative stress; Pattern recognition; Peroxidation; Prefrontal cortex; Quinolines - therapeutic use; Science; Science (multidisciplinary); Secretase; Social interactions; Streptozocin; Triazoles - therapeutic use; β-Site APP-cleaving enzyme 1; β-Site APP-cleaving enzymes
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-43532-9

Alzheimer’s disease (AD) is a multifactorial pathology characterized by amyloid deposits, neurofibrillary formation, oxidative stress and cholinergic system dysfunction. In this sense, here we report the rational design of a multi-target directed ligand (MTDL) for AD based on virtual screening and bioinformatic analyses, exploring the molecular targets β-secretase (BACE-1), glycogen synthase kinase-3β (GSK-3β) and acetylcholinesterase (AChE). After this screening, the compound with higher molecular docking affinity was selected, the 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide(QTC-4-MeOBnE). To further our studies, the protective effect of QTC-4-MeOBnE (0.1 and 1 mg/kg for 20 days) on STZ-induced sporadic AD mice was determined. QTC-4-MeOBnE pretreatment attenuated cognitive and memory deficit induced by STZ in an object recognition test, Y-maze, social recognition test and step-down passive avoidance. The mechanisms underlying this action might be attributed to the reduction of lipid peroxidation and reactive species formation in the prefrontal cortex and hippocampus of mice submitted to STZ. In addition, QTC-4-MeOBnE pretreatment abolished the up-regulation of AChE activity and the overexpression of GSK 3β and genes involved in amyloid cascade such as BACE-1, protein precursor amyloid, у-secretase, induced by STZ. Moreover, toxicological parameters were not modified by QTC-4-MeOBnE chronic treatment. This evidence suggests that QTC-4-MeOBnE exerts its therapeutic effect through multiple pathways involved in AD.