Open AccessMultiple mechanisms of dimethyl fumarate in amyloid β‐induced neurotoxicity in human neuronal cells
Author(s) -
Campolo Michela,
Casili Giovanna,
Lanza Marika,
Filippone Alessia,
Paterniti Irene,
Cuzzocrea Salvatore,
Esposito Emanuela
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13358
Subject(s) - dimethyl fumarate , oxidative stress , neuroprotection , chemistry , pharmacology , ex vivo , viability assay , neurotoxicity , in vivo , heme oxygenase , amyloid beta , biochemistry , senile plaques , neurotoxin , superoxide dismutase , in vitro , alzheimer's disease , medicine , biology , toxicity , heme , enzyme , pathology , immunology , disease , peptide , microbiology and biotechnology , organic chemistry , multiple sclerosis
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 ‐ SY 5Y 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 Aβ 1‐42 (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 (Mn SOD ) 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.