Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer's Disease.

Autor: Ettcheto M; Departament de Farmacología, Toxicologia i Quimica Terapéutica, Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain.; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Unitat de Bioquímica i Biotecnologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain.; Institut de Neurociencias, Universitat de Barcelona, Barcelona, Spain., Sánchez-López E; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Unitat de Farmacia, Tecnologia Farmacèutica i Fisico-química, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, Spain.; Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain., Gómez-Mínguez Y; Departament de Farmacología, Toxicologia i Quimica Terapéutica, Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain., Cabrera H; Departament de Farmacología, Toxicologia i Quimica Terapéutica, Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain., Busquets O; Departament de Farmacología, Toxicologia i Quimica Terapéutica, Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain.; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Unitat de Bioquímica i Biotecnologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain.; Institut de Neurociencias, Universitat de Barcelona, Barcelona, Spain., Beas-Zarate C; Departamento de Biología Celular y Molecular, C.U.C.B.A, Universidad de Guadalajara and División de Neurociencias, Sierra Mojada 800, Col. Independencia, 44340, Guadalajara, Jalisco, Mexico., García ML; Unitat de Farmacia, Tecnologia Farmacèutica i Fisico-química, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, Spain.; Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain., Carro E; Neurodegenerative Disorders Group, Instituto de Investigacion Hospital 12 de Octubre (i + 12), Madrid, Spain., Casadesus G; Department of Biological Sciences, Kent State University, Kent, OH, USA., Auladell C; Departament de Biologia Cel·lular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain., Vázquez Carrera M; Departament de Farmacología, Toxicologia i Quimica Terapéutica, Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain.; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain.; Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain., Folch J; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Unitat de Bioquímica i Biotecnologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain., Camins A; Departament de Farmacología, Toxicologia i Quimica Terapéutica, Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain. camins@ub.edu.; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. camins@ub.edu.; Institut de Neurociencias, Universitat de Barcelona, Barcelona, Spain. camins@ub.edu.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2018 Sep; Vol. 55 (9), pp. 7327-7339. Date of Electronic Publication: 2018 Feb 05.
DOI: 10.1007/s12035-018-0868-4
Abstrakt: There is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer's disease (AD). However, the molecular mechanisms through which obesity interacts with β-amyloid (Aβ) to promote cognitive decline remains poorly understood. Memantine (MEM), a N-methyl-D-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity. Therefore, the present research aims to elucidate the effects of MEM on familial AD HFD-induced insulin resistance and learning and memory impairment. Furthermore, it aspires to determine the possible underlying mechanisms that connect AD to T2DM. Wild type and APPswe/PS1dE9 mice were used in this study. The animals were fed with either chow or HFD until 6 months of age, and they were treated with MEM-supplemented water (30 mg/kg) during the last 12 weeks. Our study demonstrates that MEM improves the metabolic consequences produced by HFD in this model of familial AD. Behavioural assessments confirmed that the treatment also improves animals learning abilities and decreases memory loss. Moreover, MEM treatment improves brain insulin signalling upregulating AKT, as well as cyclic adenosine monophosphate response element binding (CREB) expression, and modulates the amyloidogenic pathway, which, in turn, reduced the accumulation of Aβ. Moreover, this drug increases the activation of molecules involved with insulin signalling in the liver, such as insulin receptor substrate 2 (IRS2), which is a key protein regulating hepatic resistance to insulin. These results provide new insight into the role of MEM not only in the occurrence of AD treatment, but also in its potential application on peripheral metabolic disorders where Aβ plays a key role, as is the case of T2DM.
Databáze: MEDLINE
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