1-(7-Chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) is a new multi-target directed ligand (MTDL) rationally designed to have affinity with beta-secretase (BACE), Glycogen Synthase Kinase 3beta (GSK3beta) and acetylcholinesterase, which are considered promising targets on the development of disease-modifying therapies against Alzheimer's Disease (AD). Previously, QTC-4-MeOBnE treatment showed beneficial effects in preclinical AD-like models by influencing in vivo neurogenesis, oxidative and inflammatory pathways. However, the biological effect and mechanism of action exerted by QTC-4-MeOBnE in AD cellular models have not been elucidated yet. Hereby we investigate the acute effect of QTC-4-MeOBnE on neuronal cells overexpressing Amyloid Protein Precursor (APP) or human tau protein, the two main features of the AD pathophysiology. When compared to the control group, QTC-4-MeOBnE treatment prevented amyloid beta (Abeta) formation through the downregulation of APP and BACE levels in APPswe-expressing cells. Furthermore, in N2a cells overexpressing human tau, QTC-4-MeOBnE reduced the levels of phosphorylated forms of tau via the modulation of the GSK3beta pathway. Taken together, our findings provide new insights into the mechanism of action exerted by QTC-4-MeOBnE in AD cellular models, and further support its potential as an interesting therapeutic strategy against AD.
Growing evidence suggests that drugs targeting neurogenesis and myelinization could be novel therapeutic targets against Alzheimer's disease (AD). Intracerebroventricular (icv) injection of streptozotocin (STZ) induces neurodegeneration through multiple mechanisms ultimately resulting in reduced adult neurogenesis. Previously, the multitarget compound QTC-4-MeOBnE (1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide) demonstrated beneficial effects in preclinical models of AD. Here we investigated its pharmacokinetics profile and the effect on memory impairments and neurodegeneration induced by STZ. Two icv injections of STZ resulted in significant cognitive and memory impairments, assessed by novel object recognition, Y-maze, social recognition, and step-down passive avoidance paradigms. These deficits were reversed in STZ-injected mice treated with QTC-4-MeOBnE. This effect was associated with reversion of neuronal loss in hippocampal dentate gyrus, reduced oxidative stress, and amelioration of synaptic function trough Na(+)/K(+) ATPase and acetylcholinesterase activities. Furthermore, brains from QTC-4-MeOBnE-treated mice had a significant increase in adult neurogenesis and remyelination through Prox1/NeuroD1 and Wnt/beta-catenin pathways. Overall, our findings support the potential anti-AD effect of QTC-4-MeOBnE through multiple pathways, all of which have been involved in the onset and progression of the disease.
Cognitive decline and memory impairment induced by disruption of cholinergic neurons and oxidative brain damage are among the earliest pathological hallmark signatures of Alzheimer's disease. Scopolamine is a post-synaptic muscarinic receptor blocker which causes impairment of cholinergic transmission resulting in cognitive deficits. Herein we investigated the effect of QTC-4-MeOBnE (1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4-carbo xamide) on memory impairments in mice chronically treated with scopolamine and the molecular mechanisms involved. Administration of scopolamine (1mg/kg) for 15 days resulted in significant impairments in working and short-term memory in mice, as assessed by the novel object recognition and the Y-maze paradigms. However, both deficits were prevented if mice receiving the scopolamine were also treated with QTC-4-MeOBnE. This effect was associated with an increase in antioxidant enzymes (superoxide dismutase and catalase), a reduction in lipid peroxidation, and an increase in Nrf2 expression. Moreover, brains from QTC-4-MeOBnE treated mice had significant decrease in acetylcholinesterase activity and glycogen synthase kinase-3beta levels, but an increase in brain-derived neurotrophic factor and Bcl-2 expression levels. Taken together our findings demonstrate that the beneficial effect of QTC-4-MeOBnE in a mouse model of scopolamine-induced memory impairment is mediated via the involvement of different molecular pathways including: oxidative stress, neuroplasticity, neuronal vulnerability and apoptosis. Our study provides further evidence on the promising therapeutic potential of QTC-4-MeOBnE as a multifactorial disease modifying drug in AD and related dementing disorders.
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 beta-secretase (BACE-1), glycogen synthase kinase-3beta (GSK-3beta) 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 3beta and genes involved in amyloid cascade such as BACE-1, protein precursor amyloid, small u, Cyrillic-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.
