The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

Abstract

Aim: Oxidative stress plays a key role in Parkinson disease (PD), and nuclear transcription factor related to NF-E2 (Nrf-2) is involved in neuroprotection against PD. The aim of the present study was to investigate a role for nuclear factor-jB (NF-jB)/Nrf-2 in the neurotherapeutic action of dimethyl fumarate (DMF) in a mouse model of PD and in vitro in SHSY-5Y cells. Results: Daily oral gavage of DMF (10, 30, and 100 mg/kg) significantly reduced neuronal cell degeneration of the dopaminergic tract and behavioral impairments induced by four injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Moreover, treatment with DMF prevented dopamine depletion, increased tyrosine hydroxylase and dopamine transporter activities, and also reduced the number of a-synucleinpositive neurons. Furthermore, DMF treatment upregulated the Nrf-2 pathway, increased NeuN + /Nrf-2 + cell number in the striatum, induced activation of manganese superoxide dismutase and heme oxygenase-1, and regulated glutathione levels. Moreover, DMF reduced interleukin 1 levels, cyclooxygenase 2 activity, and nitrotyrosine neuronal nitrite oxide synthase expression. This treatment also modulated microglia activation, restored nerve growth factor levels, and preserved microtubule-associated protein 2 alterations. The protective effects of DMF treatment, via Nrf-2, were confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline.Innovation: These findings demonstrate that DMF, both in a mouse model of PD and in vitro, provides, via regulation of the NF-jB/Nrf-2 pathway, novel cytoprotective modalities that further augment the natural antioxidant response in neurodegenerative and inflammatory disease models. Conclusion: These results support the thesis that DMF may constitute a promising therapeutic target for the treatment of PD. Antioxid. Redox Signal. 27, 453-471.

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

“…Newly, it was identified that insufficient Nrf2 activation in humans is linked to chronic diseases such as PD , AD and amyotrophic lateral sclerosis . Our findings provide elucidation of the molecular mechanisms involved in the neuroprotective action of DMF, evidencing the importance of the cell survival signalling pathways regulated by Nrf2 in term of oxidative stress.…”

“…Recent experimental studies have shown that DMF exerts beneficial effects in preclinical models of neuroinflammation and neurodegeneration : in vitro, it has been shown to protect SH‐SY5Y cells against 6‐OHDA‐induced neurotoxicity and the brain from oxidative stress via Nrf‐2‐dependent mechanisms . Moreover, in an in vivo model of Parkinson, DMF significantly reduced neuronal degeneration of dopaminergic tract and behavioural impairments .…”

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.…”

Effect of quercetin on the brain-derived neurotrophic factor gene expression in the rat brain

“…Many studies state that oxidative stress could be the major cause of neurodegenerative disorders such as Parkinson and Alzheimer's disease (26,27). In neuronal culture, quercetin increases survival against oxidative insults and appears important for neuronal protection (28).…”