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Open Access 01-12-2020 | Migraine | Research

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

Authors: Giovanna Casili, Marika Lanza, Alessia Filippone, Michela Campolo, Irene Paterniti, Salvatore Cuzzocrea, Emanuela Esposito

Published in: Journal of Neuroinflammation | Issue 1/2020

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.

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Agosti R. Migraine burden of disease: from the patient's experience to a socio-economic view. Headache. 2018;58(Suppl 1):17–32.PubMed

Maleki N, Androulakis XM. Is there any MRI pattern that discriminates female from male migraine patients? Front Neurol. 2019;10:961.PubMedPubMedCentral

Mulder EJ, Van Baal C, Gaist D, Kallela M, Kaprio J, Svensson DA, Nyholt DR, Martin NG, MacGregor AJ, Cherkas LF, et al. Genetic and environmental influences on migraine: a twin study across six countries. Twin Res. 2003;6:422–31.PubMed

Reddy DS. The pathophysiological and pharmacological basis of current drug treatment of migraine headache. Expert Rev Clin Pharmacol. 2013;6:271–88.PubMed

Lupi C, Benemei S, Guerzoni S, Pellesi L, Negro A. Pharmacokinetics and pharmacodynamics of new acute treatments for migraine. Expert Opin Drug Metab Toxicol. 2019;15:189–98.PubMed

Rujan RM, Reynolds CA. Calcitonin gene-related peptide antagonists and therapeutic antibodies. Handb Exp Pharmacol. 2019;255:169–92.PubMed

Hay DL, Walker CS. CGRP and its receptors. Headache. 2017;57:625–36.PubMed

Edvinsson L. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol. 2015;80:193–9.PubMedPubMedCentral

The Lancet N. Complicated decisions on new migraine-prevention therapies. Lancet Neurol. 2019;18:221.

10.

Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltran E, Vigneri S, Edvinsson L, Maassen Van Den Brink A, European Headache Federation School of Advanced S. Blocking CGRP in migraine patients—a review of pros and cons. J Headache Pain. 2017;18:96.PubMedPubMedCentral

11.

Borkum JM. Migraine triggers and oxidative stress: a narrative review and synthesis. Headache. 2016;56:12–35.PubMed

12.

de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM. Molecular genetics of migraine. Hum Genet. 2009;126:115–32.PubMed

13.

Kowalska M, Prendecki M, Kozubski W, Lianeri M, Dorszewska J. Molecular factors in migraine. Oncotarget. 2016;7:50708–18.PubMedPubMedCentral

14.

Geyik S, Altunisik E, Neyal AM, Taysi S. Oxidative stress and DNA damage in patients with migraine. J Headache Pain. 2016;17:10.PubMedPubMedCentral

15.

Belcher JD, Chen C, Nguyen J, Zhang P, Abdulla F, Nguyen P, Killeen T, Xu P, O'Sullivan G, Nath KA, Vercellotti GM. Control of oxidative stress and inflammation in sickle cell disease with the Nrf2 activator dimethyl Fumarate. Antioxid Redox Signal. 2017;26:748–62.PubMedPubMedCentral

16.

Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372:1463–72.PubMed

17.

Bomprezzi R. Dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis: an overview. Ther Adv Neurol Disord. 2015;8:20–30.PubMedPubMedCentral

18.

Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284:13291–5.PubMedPubMedCentral

19.

Di W, Shi X, Lv H, Liu J, Zhang H, Li Z, Fang Y. Activation of the nuclear factor E2-related factor 2/anitioxidant response element alleviates the nitroglycerin-induced hyperalgesia in rats. J Headache Pain. 2016;17:99.PubMedPubMedCentral

20.

Di Clemente L, Coppola G, Magis D, Gerardy PY, Fumal A, De Pasqua V, Di Piero V, Schoenen J. Nitroglycerin sensitises in healthy subjects CNS structures involved in migraine pathophysiology: evidence from a study of nociceptive blink reflexes and visual evoked potentials. Pain. 2009;144:156–61.PubMed

21.

Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001;358:1668–75.PubMed

22.

Bates EA, Nikai T, Brennan KC, Fu YH, Charles AC, Basbaum AI, Ptacek LJ, Ahn AH. Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia. 2010;30:170–8.PubMedPubMedCentral

23.

Dubey D, Kieseier BC, Hartung HP, Hemmer B, Warnke C, Menge T, Miller-Little WA, Stuve O. Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. Expert Rev Neurother. 2015;15:339–46.PubMed

24.

Litjens NH, Burggraaf J, van Strijen E, van Gulpen C, Mattie H, Schoemaker RC, van Dissel JT, Thio HB, Nibbering PH. Pharmacokinetics of oral fumarates in healthy subjects. Br J Clin Pharmacol. 2004;58:429–32.PubMedPubMedCentral

25.

Wang ZQ, Porreca F, Cuzzocrea S, Galen K, Lightfoot R, Masini E, Muscoli C, Mollace V, Ndengele M, Ischiropoulos H, Salvemini D. A newly identified role for superoxide in inflammatory pain. J Pharmacol Exp Ther. 2004;309:869–78.PubMed

26.

Fu H, Fang P, Zhou HY, Zhou J, Yu XW, Ni M, Zheng JY, Jin Y, Chen JG, Wang F, Hu ZL. Acid-sensing ion channels in trigeminal ganglion neurons innervating the orofacial region contribute to orofacial inflammatory pain. Clin Exp Pharmacol Physiol. 2016;43:193–202.PubMed

27.

Raboisson P, Dallel R. The orofacial formalin test. Neurosci Biobehav Rev. 2004;28:219–26.PubMed

28.

Yamamoto T, Nozaki-Taguchi N, Chiba T. Analgesic effect of intrathecally administered orexin-a in the rat formalin test and in the rat hot plate test. Br J Pharmacol. 2002;137:170–6.PubMedPubMedCentral

29.

Sufka KJ, Staszko SM, Johnson AP, Davis ME, Davis RE, Smitherman TA. Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats. J Headache Pain. 2016;17:40.PubMedPubMedCentral

30.

Tureyen K, Vemuganti R, Sailor KA, Dempsey RJ. Infarct volume quantification in mouse focal cerebral ischemia: a comparison of triphenyltetrazolium chloride and cresyl violet staining techniques. J Neurosci Methods. 2004;139:203–7.PubMed

31.

Casili G, Campolo M, Paterniti I, Lanza M, Filippone A, Cuzzocrea S, Esposito E. Dimethyl fumarate attenuates neuroinflammation and neurobehavioral deficits induced by experimental traumatic brain injury. J Neurotrauma. 2018;35:1437–51.PubMed

32.

Campolo M, Ahmad A, Crupi R, Impellizzeri D, Morabito R, Esposito E, Cuzzocrea S. Combination therapy with melatonin and dexamethasone in a mouse model of traumatic brain injury. J Endocrinol. 2013;217:291–301.PubMed

33.

Capuano A, De Corato A, Lisi L, Tringali G, Navarra P, Dello Russo C. Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology. Mol Pain. 2009;5:43.PubMedPubMedCentral

34.

Campolo M, Casili G, Biundo F, Crupi R, Cordaro M, Cuzzocrea S, Esposito E. The neuroprotective effect of dimethyl Fumarate in an MPTP-mouse model of Parkinson's disease: involvement of reactive oxygen species/nuclear factor-kappaB/nuclear transcription factor related to NF-E2. Antioxid Redox Signal. 2017;27:453–71.PubMedPubMedCentral

35.

Siracusa R, Paterniti I, Impellizzeri D, Cordaro M, Crupi R, Navarra M, Cuzzocrea S, Esposito E. The Association of Palmitoylethanolamide with Luteolin decreases neuroinflammation and stimulates autophagy in Parkinson’s disease model. CNS Neurol Disord Drug Targets. 2015;14:1350–65.PubMed

36.

Abdallah K, Artola A, Monconduit L, Dallel R, Luccarini P. Bilateral descending hypothalamic projections to the spinal trigeminal nucleus caudalis in rats. PLoS One. 2013;8:e73022.PubMedPubMedCentral

37.

Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain. 2013;154(Suppl 1S):44–53.

38.

Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A. Characterization of a novel model of chronic migraine. Pain. 2014;155:269–74.PubMed

39.

Furman JM, Balaban CD, Jacob RG, Marcus DA. Migraine-anxiety related dizziness (MARD): a new disorder? J Neurol Neurosurg Psychiatry. 2005;76:1–8.PubMedPubMedCentral

40.

Minen MT, Begasse De Dhaem O, Kroon Van Diest A, Powers S, Schwedt TJ, Lipton R, Silbersweig D. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016;87:741–9.PubMed

41.

Wu Y, Hallett M. Photophobia in neurologic disorders. Transl Neurodegener. 2017;6:26.PubMedPubMedCentral

42.

Alp R, Selek S, Alp SI, Taskin A, Kocyigit A. Oxidative and antioxidative balance in patients of migraine. Eur Rev Med Pharmacol Sci. 2010;14:877–82.PubMed

43.

Mark W. Weatherall. The diagnosis and treatment of chronic migraine. Ther Adv Chronic Dis. 2015;6(3):115–123.

44.

Lee I, Kim HK, Kim JH, Chung K, Chung JM. The role of reactive oxygen species in capsaicin-induced mechanical hyperalgesia and in the activities of dorsal horn neurons. Pain. 2007;133:9–17.PubMedPubMedCentral

45.

Takano T, Tian GF, Peng W, Lou N, Lovatt D, Hansen AJ, Kasischke KA, Nedergaard M. Cortical spreading depression causes and coincides with tissue hypoxia. Nat Neurosci. 2007;10:754–62.PubMed

46.

Viggiano A, Viggiano E, Valentino I, Monda M, Viggiano A, De Luca B. Cortical spreading depression affects reactive oxygen species production. Brain Res. 2011;1368:11–8.PubMed

47.

Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem. 1992;59:1609–23.PubMed

48.

Tozzi-Ciancarelli MG, De Matteis G, Di Massimo C, Marini C, Ciancarelli I, Carolei A. Oxidative stress and platelet responsiveness in migraine. Cephalalgia. 1997;17:580–4.PubMed

49.

Bockowski L, Sobaniec W, Kulak W, Smigielska-Kuzia J. Serum and intraerythrocyte antioxidant enzymes and lipid peroxides in children with migraine. Pharmacol Rep. 2008;60:542–8.PubMed

50.

Tuncel D, Tolun FI, Gokce M, Imrek S, Ekerbicer H. Oxidative stress in migraine with and without aura. Biol Trace Elem Res. 2008;126:92–7.PubMed

51.

Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol. 2004;37:139–43.PubMed

52.

Sandberg M, Patil J, D'Angelo B, Weber SG, Mallard C. NRF2-regulation in brain health and disease: implication of cerebral inflammation. Neuropharmacology. 2014;79:298–306.PubMed

53.

Traub J, Traffehn S, Ochs J, Hausser-Kinzel S, Stephan S, Scannevin R, Bruck W, Metz I, Weber MS. Dimethyl fumarate impairs differentiated B cells and fosters central nervous system integrity in treatment of multiple sclerosis. Brain Pathol. 2019;29(5):640–57.PubMedPubMedCentral

54.

Ellrichmann G, Petrasch-Parwez E, Lee DH, Reick C, Arning L, Saft C, Gold R, Linker RA. Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington's disease. PLoS One. 2011;6:e16172.PubMedPubMedCentral

55.

Yao Y, Miao W, Liu Z, Han W, Shi K, Shen Y, Li H, Liu Q, Fu Y, Huang D, Shi FD. Dimethyl fumarate and monomethyl fumarate promote post-ischemic recovery in mice. Transl Stroke Res. 2016;7:535–47.PubMedPubMedCentral

56.

Hiruma-Lima CA, Gracioso JS, Bighetti EJ, Germonsen Robineou L, Souza Brito AR. The juice of fresh leaves of Boerhaavia diffusa L. (Nyctaginaceae) markedly reduces pain in mice. J Ethnopharmacol. 2000;71:267–74.PubMed

57.

Oh K, Cho SJ, Chung YK, Kim JM, Chu MK. Erratum to: combination of anxiety and depression is associated with an increased headache frequency in migraineurs: a population-based study. BMC Neurol. 2016;16:51.PubMedPubMedCentral

58.

Kawasaki A, Purvin VA. Photophobia as the presenting visual symptom of chiasmal compression. J Neuroophthalmol. 2002;22:3–8.PubMed

59.

Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–84.PubMedPubMedCentral

60.

Robert C, Bourgeais L, Arreto CD, Condes-Lara M, Noseda R, Jay T, Villanueva L. Paraventricular hypothalamic regulation of trigeminovascular mechanisms involved in headaches. J Neurosci. 2013;33:8827–40.PubMedPubMedCentral

61.

Burstein R, Jakubowski M, Garcia-Nicas E, Kainz V, Bajwa Z, Hargreaves R, Becerra L, Borsook D. Thalamic sensitization transforms localized pain into widespread allodynia. Ann Neurol. 2010;68:81–91.PubMedPubMedCentral

62.

Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol. 1998;79:964–82.PubMed

63.

Pardutz A, Multon S, Malgrange B, Parducz A, Vecsei L, Schoenen J. Effect of systemic nitroglycerin on CGRP and 5-HT afferents to rat caudal spinal trigeminal nucleus and its modulation by estrogen. Eur J Neurosci. 2002;15:1803–9.PubMed

64.

Li Y, Zhang Q, Qi D, Zhang L, Yi L, Li Q, Zhang Z. Valproate ameliorates nitroglycerin-induced migraine in trigeminal nucleus caudalis in rats through inhibition of NF-small ka, CyrillicB. J Headache Pain. 2016;17:49.PubMedPubMedCentral

65.

Tassorelli C, Greco R, Morazzoni P, Riva A, Sandrini G, Nappi G. Parthenolide is the component of tanacetum parthenium that inhibits nitroglycerin-induced Fos activation: studies in an animal model of migraine. Cephalalgia. 2005;25:612–21.PubMed

66.

Reuter U, Chiarugi A, Bolay H, Moskowitz MA. Nuclear factor-kappaB as a molecular target for migraine therapy. Ann Neurol. 2002;51:507–16.PubMed

67.

Perry CJ, Blake P, Buettner C, Papavassiliou E, Schain AJ, Bhasin MK, Burstein R. Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: implications for extracranial origin of headache. Ann Neurol. 2016;79:1000–13.PubMedPubMedCentral

68.

Conti P, D'Ovidio C, Conti C, Gallenga CE, Lauritano D, Caraffa A, Kritas SK, Ronconi G. Progression in migraine: role of mast cells and pro-inflammatory and anti-inflammatory cytokines. Eur J Pharmacol. 2019;844:87–94.PubMed

69.

Singh N, Saha L, Kumari P, Singh J, Bhatia A, Banerjee D, Chakrabarti A. Effect of dimethyl fumarate on neuroinflammation and apoptosis in pentylenetetrazol kindling model in rats. Brain Res Bull. 2019;144:233–45.PubMed

70.

Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, Tanaka N, Moriguchi T, Motohashi H, Nakayama K, Yamamoto M. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 2016;7:11624.PubMedPubMedCentral

71.

Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47:1304–9.PubMedPubMedCentral

72.

Hammer A, Waschbisch A, Kuhbandner K, Bayas A, Lee DH, Duscha A, Haghikia A, Gold R, Linker RA. The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis. Ann Clin Transl Neurol. 2018;5:668–76.PubMedPubMedCentral

Title: Dimethyl fumarate alleviates the nitroglycerin (NTG)-induced migraine in mice
Authors: Giovanna Casili
Marika Lanza
Alessia Filippone
Michela Campolo
Irene Paterniti
Salvatore Cuzzocrea
Emanuela Esposito
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Migraine
Nitroglycerin
Sumatriptan
Dimethyl Fumarate
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-01736-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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