RESUMO
Alzheimer's disease (AD) is a neurodegenerative disease with no cure nowadays; there is no treatment either to prevent or to stop its progression. In vitro studies suggested that tert-butyl-(4-hydroxy-3-((3-(2-methylpiperidin-yl)propyl)carbamoyl)phenyl) carbamate named the M4 compound can act as both ß-secretase and an acetylcholinesterase inhibitor, preventing the amyloid beta peptide (Aß) aggregation and the formation of fibrils (fAß) from Aß1-42. This work first aimed to assess in in vitro studies to see whether the death of astrocyte cells promoted by Aß1-42 could be prevented. Second, our work investigated the ability of the M4 compound to inhibit amyloidogenesis using an in vivo model after scopolamine administration. The results showed that M4 possesses a moderate protective effect in astrocytes against Aß1-42 due to a reduction in the TNF-α and free radicals observed in cell cultures. In the in vivo studies, however, no significant effect of M4 was observed in comparison with a galantamine model employed in rats, in which case this outcome was attributed to the bioavailability of M4 in the brain of the rats.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Carbamatos , Fármacos Neuroprotetores , Fragmentos de Peptídeos/metabolismo , Escopolamina/efeitos adversos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Animais , Astrócitos/patologia , Carbamatos/química , Carbamatos/farmacologia , Modelos Animais de Doenças , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ratos , Escopolamina/farmacologiaRESUMO
The increase of amyloid beta (Aß) release and hyperphosphorylation of Tau protein represents the main events related to Alzheimer's disease (AD). Furthermore, the sporadic type represents the most common form of AD. Therefore, the establishment of a non-transgenic animal model that resembles the characteristics of the disease is of particular importance. Scopolamine has been linked to increases in both Aß production and oxidative stress in rat and mice brains. Thus, the purpose of the present work was to identify changes in biomarkers that are related to AD after chronic administration of scopolamine (2 mg/kg i.p., during 6 and 12 weeks) to male Wistar rats. The results showed increased Aß deposition at rat hippocampus which could be due to an increase of ß-site amyloid-ß-protein precursor cleaving enzyme 1 (BACE1) expression and activity. These findings could be related to the increase of glycogen synthase kinase 3 phosphorylated (GSK3ßP9) expression. Finally, the establishment of a state of oxidative stress in groups treated with scopolamine was demonstrated by an increase in free radical content and MDA levels. The present study facilitates our understanding of the changes that occur in biomolecules related to AD in Wistar rats after the chronic administration of scopolamine.