Miren Ettcheto1,2,3,4, Elena Sánchez-Lopez5,6,7, Amanda Cano5,6,7,8, Marina Carrasco9,5,10,11, Katherine Herrera10,12, Patricia R Manzine13, Triana Espinosa-Jimenez9,5,10, Oriol Busquets14, Ester Verdaguer5,10,12, Jordi Olloquequi15, Carme Auladell5,10,12, Jaume Folch5,11, Antoni Camins9,5,10. 1. Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain. mirenettcheto@ub.edu. 2. Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. mirenettcheto@ub.edu. 3. Institute of Neuroscience, University of Barcelona, Barcelona, Spain. mirenettcheto@ub.edu. 4. Unitat de Farmacologia I Farmacognòsia, Facultat de Farmàcia I Ciències de L'Alimentació, Universitat de Barcelona, Av. Joan XXIII 27/31, 08028, Barcelona, Spain. mirenettcheto@ub.edu. 5. Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. 6. Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain. 7. Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain. 8. Research Center and Memory Clinic, Fundació ACE. Institut Català de Neurociències Aplicades - International University of Catalunya (UIC), Barcelona, Spain. 9. Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain. 10. Institute of Neuroscience, University of Barcelona, Barcelona, Spain. 11. Department of Biochemistry and Biotechnology, Faculty of Medicine and Life Science, University Rovira I Virgili, Reus, Spain. 12. Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain. 13. Department of Gerontology, Federal University of São Carlos (UFSCar), São Carlos, 13565-905, Brazil. 14. Dominick P. Purpura Department of Neurosciences, Albert Einstein College of Medicine, New York City (10461), USA. 15. Laboratory of Cellular and Molecular Pathology, Facultad de Ciencias de La Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile.
Abstract
BACKGROUND: Several studies stablished a relationship between metabolic disturbances and Alzheimer´s disease (AD) where inflammation plays a pivotal role. However, mechanisms involved still remain unclear. In the present study, we aimed to evaluate central and peripheral effects of dexibuprofen (DXI) in the progression of AD in APPswe/PS1dE9 (APP/PS1) female mice, a familial AD model, fed with high fat diet (HFD). Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice, at 6 months. Moreover, mice were divided into subgroups to which were administered drinking water or water supplemented with DXI (20 mg kg-1 d-1) for 3 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-ITT) were performed to evaluate peripheral parameters and also behavioral tests to determine cognitive decline. Moreover, molecular studies such as Western blot and RT-PCR were carried out in liver to confirm metabolic effects and in hippocampus to analyze several pathways considered hallmarks in AD. RESULTS: Our studies demonstrate that DXI improved metabolic alterations observed in transgenic animals fed with HFD in vivo, data in accordance with those obtained at molecular level. Moreover, an improvement of cognitive decline and neuroinflammation among other alterations associated with AD were observed such as beta-amyloid plaque accumulation and unfolded protein response. CONCLUSIONS: Collectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.
BACKGROUND: Several studies stablished a relationship between metabolic disturbances and Alzheimer´s disease (AD) where inflammation plays a pivotal role. However, mechanisms involved still remain unclear. In the present study, we aimed to evaluate central and peripheral effects of dexibuprofen (DXI) in the progression of AD in APPswe/PS1dE9 (APP/PS1) female mice, a familial AD model, fed with high fat diet (HFD). Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice, at 6 months. Moreover, mice were divided into subgroups to which were administered drinking water or water supplemented with DXI (20 mg kg-1 d-1) for 3 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-ITT) were performed to evaluate peripheral parameters and also behavioral tests to determine cognitive decline. Moreover, molecular studies such as Western blot and RT-PCR were carried out in liver to confirm metabolic effects and in hippocampus to analyze several pathways considered hallmarks in AD. RESULTS: Our studies demonstrate that DXI improved metabolic alterations observed in transgenic animals fed with HFD in vivo, data in accordance with those obtained at molecular level. Moreover, an improvement of cognitive decline and neuroinflammation among other alterations associated with AD were observed such as beta-amyloid plaque accumulation and unfolded protein response. CONCLUSIONS: Collectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.
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