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

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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 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-carboxamide) 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-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.
Funding Information
  • Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
  • Funda??o de Amparo ? Pesquisa do Estado do Rio Grande do Sul (04/2018 - DOCFIX 18/2551-0000511-8, 16/2551-0000240-1, 17/2551-00011046-9)
  • Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (001, 04/2018 - DOCFIX 18/2551-0000511-8)

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