Dimethyl fumarate alleviates the nitroglycerin (NTG)-induced migraine in mice

Abstract

Background: Oxidative stress and inflammatory pathways are involved in migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the fumaric acid esters (FAEs), dimethyl fumarate, nuclear factor E2-related factor 2/antioxidant response element (Nrf-2/ARE) pathway-mediated, in regulating the hypersensitivity in a mouse model of nitroglycerine (NTG)-induced migraine. Methods: Mice were orally administered with DMF at the doses of 10, 30, and 100 mg/kg, 5 min after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brain and behavioral tests after 4 h by NTG-migraine induction. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Nrf-2, manganese superoxide dismutase (Mn-SOD), and heme-oxygenase-1 (HO-1) were detected by Western blot. Tail flick, hot plate, orofacial formalin, and photophobia tests were used to evaluate migraine-like pain and migraine-related light sensitivity. Moreover, we evaluate Nrf-2-dependent mechanism by the in vitro stimulation of cells extracted by trigeminal ganglia with diethylenetriamine/nitric oxide (DETA/NO), a nitric oxide (NO) donor. The cells were pre-treated with DMF and an antagonist of Nrf-2, trigonelline (TR) 2 h before DETA/NO stimulation. Results: DMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF-κB and Nrf-2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache was significantly reduced. The protective effect of DMF treatment, via Nrf-2, was confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. Cytotoxicity, iNOS, and MnSOD expression were evaluated. Conclusion: These results provided the evidence that DMF, by Nrf-2 modulation, has a protective effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.

Antioxidant and Anti-inflammatory Effect of Nrf2 Inducer Dimethyl Fumarate in Neurodegenerative Diseases

“…Moreover, an in vitro study investigated the multiple mechanisms of DMF [ 10 ]; for the experiment, were used SH-SY5Y human neuroblastoma cell lines stimulated with amyloid-beta (Ab). The form of 42-amino acid of this peptide, Ab (1–42), has been shown to contribute to the pathogenesis of AD, and is also linked to oxidative stress and inflammation in the CNS [ 114 ].…”

“…In particular, Nrf2 has been proposed as a new pharmacological target in neuroinflammatory pathologies, including NDs [ 9 ]. Many papers highlighted the importance of molecules with antioxidant activities for the treatment of NDs, such as the fumaric acid esters (FAEs), where DMF represents the most pharmacologically effective molecule [ 10 ]. It has been shown that DMF acts as an Nrf2 activator, able to stimulate a cellular defense to protect neurons from ROS-induced damage [ 11 ].…”

The Inhibition of Prolyl Oligopeptidase as New Target to Counteract Chronic Venous Insufficiency: Findings in a Mouse Model

“…Total cytosolic and nuclear extracts were prepared, as previously described [ 26 ], on saphene veins. The following primary antibodies were used: anti- IL-1β (Santa Cruz Biotechnology, Dallas, TX, USA, 1:500 #sc12742, D.B.A, Milan, Italy), anti-TNF-α (Santa Cruz Biotechnology; 1:500 #sc52746), anti-TGFβ1 (Santa Cruz Biotechnology, 1:500 #sc130348, D.B.A, Milan, Italy), anti-VEGF (Santa Cruz Biotechnology; 1:1000 #sc7269), anti- αSMA (Santa Cruz Biotechnology; 1:500 #sc53015) and anti-prolyl endopeptidase (Abcam; 1:1000,#ab58988) in 1× phosphate-buffer saline (Biogenerica srl, Catania, Italy), 5% w/v non-fat dried milk, 0.1% Tween-20 at 4 °C overnight.…”

Emerging Therapeutic Applications for Fumarates

“…In a rat model of arthritis, a single intraperitoneal dose of MMF dose-dependently alleviated pressure hyperalgesia, as well as unevoked vocalizations, a sign of spontaneous pain [60]. In a nitroglycerine-induced migraine model, acute oral administration of DMF attenuated heat hyperalgesia and photophobia [61]. DMF also increased levels of NRF2, SOD2, and HO-1, while decreasing NFκB p65 levels in the whole brain [61].…”

“…In a nitroglycerine-induced migraine model, acute oral administration of DMF attenuated heat hyperalgesia and photophobia [61]. DMF also increased levels of NRF2, SOD2, and HO-1, while decreasing NFκB p65 levels in the whole brain [61]. However, the therapeutic mechanisms of action in both models remain to be defined.…”