Multiple mechanisms of dimethyl fumarate in amyloid β-induced neurotoxicity in human neuronal cells

Autor: Marika Lanza, Emanuela Esposito, Giovanna Casili, Salvatore Cuzzocrea, Alessia Filippone, Irene Paterniti, Michela Campolo
Rok vydání: 2017
Předmět:
0301 basic medicine
Dimethyl Fumarate
Pharmacology
medicine.disease_cause
Hippocampus
Antioxidants
Mice
chemistry.chemical_compound
0302 clinical medicine
oxidative stress
Senile plaques
Phosphorylation
RNA
Small Interfering
Neurons
chemistry.chemical_classification
Dimethyl fumarate
NF-kappa B
Alzheimer's disease
Neuroprotection
Neuroprotective Agents
Molecular Medicine
Original Article
Cell Survival
NF-E2-Related Factor 2
Neurotoxins
tau Proteins
Oxidative phosphorylation
Nrf2
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Humans
Inflammation
Reactive oxygen species
Amyloid beta-Peptides
Nf‐kB
Neurotoxicity
tau hyper‐phosphorylation
Original Articles
Cell Biology
medicine.disease
030104 developmental biology
chemistry
Alzheimer's disease
dimethyl fumarate
Nf-kB
Nrf2
oxidative stress
tau hyper-phosphorylation
Molecular Medicine
Cell Biology
Reactive Oxygen Species
030217 neurology & neurosurgery
Oxidative stress
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-1838
DOI: 10.1111/jcmm.13358
Popis: Alzheimer disease (AD) is characterized by a complex heterogeneity of pathological changes, and any therapeutic approach categorically requires a multi‐targeted way. It has been demonstrated that together with the hallmarks of the disease such as neurofibrillary tangles and senile plaques, oxidative and inflammatory stress covered an important role. Dimethyl fumarate (DMF) is an orally bioavailable methyl ester of fumaric acid and activator of Nrf2 with potential neuroprotective and immunomodulating activities. Therefore, the aim of the present work was to evaluate the potential beneficial effects of DMF, compared with its active metabolite monomethyl fumarate (MMF) (both at 30 μM) in an in vitro Alzheimer's model using SH‐SY5Y human neuroblastoma cell lines stimulated with amyloid‐beta (Aβ). Moreover, the effect of DMF, compared with MMF, was evaluate by an ex vivo model using organotypic hippocampal slice cultures stimulated with Aβ1‐42 (1 μg/ml), to better understand its action in a pathological setting. In both models, DMF pre‐treatment (30 μM) preserved cellular viability from Aβ stimulation, reducing tau hyper‐phosphorylation, much more efficiently then MMF (30 μM). Moreover, DMF was able to induce an activation of manganese superoxide dismutase (MnSOD) and heme‐oxygenase‐1 (HO‐1), decreasing the severity of oxidative stress. Our results showed important multi‐protective effects of DMF pre‐treatment from Aβ stimulation both in in vitro and ex vivo models, highlighting an Nrf2/NF‐κB‐dependent mechanism, which could provide a valuable support to the therapies for neurodegenerative diseases today.
Databáze: OpenAIRE
Externí odkaz: