QTC-4-MeOBnE Rescues Scopolamine-Induced Memory Deficits in Mice by Targeting Oxidative Stress, Neuronal Plasticity, and Apoptosis.

Abstract

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 postsynaptic 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-carboxamide) on memory impairments in mice chronically treated with scopolamine and the molecular mechanisms involved. Administration of scopolamine (1 mg/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 a significant decrease in acetylcholinesterase activity and glycogen synthase kinase-3β 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.

• Authors: Mariana G Fronza, Rodolfo Baldinotti, Jenifer Fetter, Manoela Sacramento, Fernanda Severo Sabedra Sousa, Fabiana K Seixas, Tiago Collares, Diego Alves, Domenico Praticò, Lucielli Savegnago
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 11 Issue 9 Pg. 1259-1269 (05 06 2020) ISSN: 1948-7193 [Electronic] United States
• PMID: 32227985 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Scopolamine
• Acetylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Animals
• Apoptosis
• Hippocampus (metabolism)
• Maze Learning
• Memory Disorders (chemically induced, drug therapy)
• Mice
• Neuronal Plasticity
• Oxidative Stress
• Scopolamine (toxicity)