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

Abstract

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.

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

“…It has also been shown to prevent hippocampal injury following ischemia, reduce edema volume, and protect BBB integrity in mouse models of stroke (Kunze et al, 2015;Yao et al, 2016;Liu et al, 2019a) as well as improve cognitive function in models of AD and subarachnoid hemorrhage (Liu et al, 2015;Majkutewicz et al, 2016;Majkutewicz et al, 2018). In addition, as mentioned previously, DMF protects against both aSyn and Ab toxicity and can reduce tau hyperphosphorylation (Lastres-Becker et al, 2016;Campolo et al, 2018;Bahn and Jo, 2019).…”

Dimethyl fumarate, a two‐edged drug: Current status and future directions

“…In TBI, DMF effect has been associated with increase in NRF2, manganese superoxide dismutase (MnSOD), and HO‐1 and a decrease in inflammation via modulation of immune response genes such as IL‐1 and TNF‐α . Similar neuroprotective roles of DMF were observed in epileptic rats, while in HD, AD and PD; all of which are characterized by oxidative stress and neuroinflammation, DMF can reduce the severity of oxidative stress by upregulating NRF2, MnSOD, and HO‐1 levels and by downregulating IL‐1 and cyclooxygenase 2 (COX‐2) levels …”

“…The therapeutic benefits of DMF have been shown in other acute and chronic neurological disorders; including stroke, traumatic brain injury (TBI), epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), which are all associated with oxidative stress and/or inflammation. DMF can induce increased expression of antioxidative genes by activating the NRF2 cellular defense machinery against oxidative stress.…”

“…The therapeutic benefits of DMF have been shown in other acute and chronic neurological disorders; including stroke, 74-76 traumatic brain injury (TBI), 77 epilepsy, 78 Alzheimer's disease (AD), 79 Parkinson's disease (PD), 80,81 and…”

Electrophiles against (Skin) Diseases: More Than Nrf2

“…In conclusion, DMF and, to a lesser extent, MMF, target and inhibit the NF-κB pathway by different NRF2-independent and -dependent mechanisms. Consequently, both pathways contribute to cytoprotection in vitro but also in vivo, as shown in a mouse model of Parkinson's disease [82,83].…”