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Inflammation

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Thymoquinone Inhibits Neurogenic Inflammation Underlying Migraine Through Modulation of Calcitonin Gene-Related Peptide Release and Stabilization of Meningeal Mast Cells in Glyceryltrinitrate-Induced Migraine Model in Rats

  • Erkan KilincEmail author
  • Fatma Tore
  • Yasar Dagistan
  • Guler Bugdayci
Original Article
  • 7 Downloads

Abstract

Two main contributors of sterile neurogenic inflammation underlying migraine pain, calcitonin gene–related peptide (CGRP), and meningeal mast cells (MMCs) play a key role in the activation of the inflammatory cascade resulting in the sensitization of trigeminal nociceptors. It is well established that phytochemical agent thymoquinone exhibits multiple anti-inflammatory effects in different in vitro and in vivo models of neuroinflammation. But its effects on the CGRP release and meningeal mast cells are unknown. In the present study, we investigated the effects of thymoquinone on the CGRP release in migraine-related strategic structures which are crucial targets for anti-migraine drugs, and on the MMCs in glyceryl trinitrate (GTN)–induced in vivo migraine model as well as in the ex vivo meningeal preparations in rats. Anti-inflammatory thymoquinone ameliorated GTN-stimulated CGRP levels in plasma, and migraine-related structures including trigeminal ganglion and brainstem; moreover, thymoquinone inhibited degranulation of MMCs and prevented the increase in the number of MMCs in GTN-induced in vivo migraine model. However, in the ex vivo meningeal preparations, thymoquinone did not inhibit the GTN-induced CGRP release from trigeminal meningeal afferents. Our findings suggest that thymoquinone mediates modulation of CGRP release in trigeminal ganglion neurons and brainstem, and stabilization of MMCs. Thus, thymoquinone may be a promising candidate to prevent the meningeal neurogenic inflammation and consequently migraine.

KEY WORDS

Neurogenic inflammation Migraine Thymoquinone Meningeal mast cells CGRP 

Notes

Funding Information

This study was supported by Abant Izzet Baysal University Scientific Research Fund (grant number 2016.08.02.1082).

Compliance with Ethical Standards

All applicable international and institutional guidelines for the care and use of animals were conformed. All procedures carried out in studies involving animals were in keeping with the ethical standards of the institution or practice at which the studies were carried out.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Koyuncu Irmak, D., E. Kilinc, and F. Tore. 2019. Shared fate of meningeal mast cells and sensory neurons in migraine. Frontiers in Cellular Neuroscience 13: 136.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Zhao, J., and D. Levy. 2015. Modulation of intracranial meningeal nociceptor activity by cortical spreading depression—a reassessment. Journal of Neurophysiology 113: 2778–2785.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Levy, D., A. Labastida-Ramirez, and A. MaassenVanDenBrink. 2018. Current understanding of meningeal and cerebral vascular function underlying migraine headache. Cephalalgia 1: 333102418771350.Google Scholar
  4. 4.
    Kilinc, E., C. Guerrero-Toro, A. Zakharov, C. Vitale, M. Gubert-Olive, K. Koroleva, A. Timonina, L.L. Luz, I. Shelukhina, R. Giniatullina, F. Tore, B.V. Safronov, and R. Giniatullin. 2017. Serotonergic mechanisms of trigeminal meningeal nociception: implications for migraine pain. Neuropharmacology 116: 160–173.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Kilinc, E., Y. Dagistan, A. Kukner, B. Yilmaz, S. Agus, G. Soyler, and F. Tore. 2018. Salmon calcitonin ameliorates migraine pain through modulation of CGRP release and dural mast cell degranulation in rats. Clinical and Experimental Pharmacology and Physiology 45: 536–546.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Dux, M., C. Will, M. Eberhardt, M.J.M. Fischer, and K. Messlinger. 2017. Stimulation of rat cranial dura mater with potassium chloride causes CGRP release into the cerebrospinal fluid and increases medullary blood flow. Neuropeptides 64: 61–68.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Kilinc, E., and C.N. Balci. 2018. An investigation of lung mast cell behavior in a rat model of migraine: implications for migraine headache. Anatolian Clinic Journal of Medical Science 23: 151–156.Google Scholar
  8. 8.
    Theoharides, T.C., I. Tsilioni, and P. Conti. 2019. Mast cells may regulate the anti-inflammatory activity of IL-37. International Journal of Molecular Sciences 20: 3701.PubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ottosson, A., and L. Edvinsson. 1997. Release of histamine from dural mast cells by substance P and calcitonin gene-related peptide. Cephalalgia 17: 166–174.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Zhang, X.C., A.M. Strassman, R. Burstein, and D. Levy. 2007. Sensitization and activation of intracranial meningeal nociceptors by mast cell mediators. The Journal of Pharmacology and Experimental Therapeutics 322: 806–812.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Levy, D., R. Burstein, V. Kainz, M. Jakubowski, and A.M. Strassman. 2007. Mast cell degranulation activates a pain pathway underlying migraine headache. PAIN 130: 166–176.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    El Gazzar, M.A. 2007. Thymoquinone suppressses in vitro production of IL-5 and IL-13 by mast cells in response to lipopolysaccharide stimulation. Inflammation Research 56: 345–351.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Taka, E., E.A. Mazzio, C.B. Goodman, et al. 2015. Anti-inflammatory effects of thymoquinone in activated BV-2 microglial cells. Journal of Neuroimmunology 286: 5–12.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Velagapudi, R., A. Kumar, H.S. Bhatia, A. el-Bakoush, I. Lepiarz, B.L. Fiebich, and O.A. Olajide. 2017. Inhibition of neuroinflammation by thymoquinone requires activation of Nrf2/ARE signalling. International Immunopharmacology 48: 17–29.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Velagapudi, R., A. El-Bakoush, I. Lepiarz, et al. 2017. AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2 microglia. Molecular and Cellular Biochemistry 435: 149–162.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Goyal, S.N., C.P. Prajapati, P.R. Gore, et al. 2017. Therapeutic potential and pharmaceutical development of thymoquinone: a multitargeted molecule of natural origin. Frontiers in Pharmacology 8: 656.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Abd El Aziz, A.E., N.S. El Sayed, and L.G. Mahran. 2011. Anti-asthmatic and anti-allergic effects of thymoquinone on airway-induced hypersensitivity in experimental animals. Journal of Applied Pharmaceutical Science 1: 109–117.Google Scholar
  18. 18.
    Chakravarty, N. 1993. Inhibition of histamine release from mast cells by nigellone. Annals of Allergy 70: 237–242.PubMedGoogle Scholar
  19. 19.
    Kanter, M., O. Coskun, and H. Uysal. 2006. The antioxidative and antihistaminic effect of Nigella sativa and its major constituent, thymoquinone on ethanol-induced gastric mucosal damage. Archives of Toxicology 80: 217–224.PubMedCrossRefGoogle Scholar
  20. 20.
    Kilinc, E., Y. Dagistan, B. Kotan, and A. Cetinkaya. 2017. Effects of Nigella sativa seeds and certain species of fungi extracts on number and activation of dural mast cells in rats. Physiology International 104: 15–24.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Greco, R., V. Gasperi, G. Sandrini, G. Bagetta, G. Nappi, M. Maccarrone, and C. Tassorelli. 2010. Alterations of the endocannabinoid system in an animal model of migraine: evaluation in cerebral areas of rat. Cephalalgia 30: 296–302.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Attoub, S., O. Sperandio, H. Raza, K. Arafat, S. al-Salam, M.A. al Sultan, M. al Safi, T. Takahashi, and A. Adem. 2013. Thymoquinone as an anticancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundamental & Clinical Pharmacology 27: 557–569.CrossRefGoogle Scholar
  23. 23.
    Kilinc, E., T. Firat, F. Tore, et al. 2015. Vasoactive intestinal peptide modulates c-Fos activity in the trigeminal nucleus and dura mater mast cells in sympathectomized rats. Journal of Neuroscience Research 93: 644–550.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Braga, V.A.V.N., G.K. Couto, M.C. Lazzarin, et al. 2015. Aerobic exercise training prevents the onset of endothelial dysfunction via increased nitric oxide bioavailability and reduced reactive oxygen species in an experimental model of menopause. PLoS One 10: e0125388.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Bree, D., and D. Levy. 2019. Intact mast cell content during mild head injury is required for development of latent pain sensitization: implications for mechanisms underlying post-traumatic headache. Pain 160: 1050–1058.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Ramachandran, R. 2018. Neurogenic inflammation and its role in migraine. Seminars in Immunopathology 40: 301–314.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Dagistan, Y., E. Kilinc, and C.N. Balci. 2019. Cervical sympathectomy modulates the neurogenic inflammatory neuropeptides following experimental subarachnoid hemorrhage in rats. Brain Research 1722: 146366.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Pedersen, S.H., R. Ramachandran, D.V. Amrutkar, S. Petersen, J. Olesen, and I. Jansen-Olesen. 2015. Mechanisms of glyceryl trinitrate provoked mast cell degranulation. Cephalalgia 35: 1287–1297.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Durham, P.L., and A.F. Russo. 1999. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. The Journal of Neuroscience 19: 3423–3429.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Cernuda-Morollón, E., D. Larrosa, C. Ramón, J. Vega, P. Martínez-Camblor, and J. Pascual. 2013. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 81: 1191–1196.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Juhasz, G., T. Zsombok, E.A. Modos, S. Olajos, B. Jakab, J. Nemeth, J. Szolcsanyi, J. Vitrai, and G. Bagdy. 2003. NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 106: 461–470.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Zhang, X.F., W.J. Zhang, C.L. Dong, W.L. Hu, Y.Y. Sun, Y. Bao, C.F. Zhang, C.R. Guo, C.Z. Wang, and C.S. Yuan. 2017. Analgesia effect of baicalein against NTG-induced migraine in rats. Biomedicine & Pharmacotherapy 90: 116–121.CrossRefGoogle Scholar
  33. 33.
    Dieterle, A., M.J. Fischer, A.S. Link, W.L. Neuhuber, and K. Messlinger. 2011. Increase in CGRP- and nNOS-immunoreactive neurons in the rat trigeminal ganglion after infusion of an NO donor. Cephalalgia 31: 31–42.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Ramachandran, R., D.K. Bhatt, and K.B. Ploug. 2014. Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation. Cephalalgia 34: 136–147.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Cascella, M., S. Bimonte, A. Barbieri, et al. 2018. Dissecting the potential roles of Nigella sativa and its constituent thymoquinone on the prevention and on the progression of Alzheimer’s disease. Frontiers in Aging Neuroscience 10: 16.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Durham, P.L., and C.V. Vause. 2010. Calcitonin gene-related peptide (CGRP) receptor antagonists in the treatment of migraine. CNS Drugs 24: 539–548.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Thalakoti, S., V.V. Patil, S. Damodaram, et al. 2007. Neuron-glia signaling in trigeminal ganglion: implications for migraine pathology. Headache 47: 1008–1023.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Iyengar, S., M.H. Ossipov, and K.W. Johnson. 2017. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain 158: 543–559.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Schwenger, N., M. Dux, R. de Col, R. Carr, and K. Messlinger. 2007. Interaction of calcitonin gene-related peptide, nitric oxide and histamine release in neurogenic blood flow and afferent activation in the rat cranial dura mater. Cephalalgia 27: 481–491.PubMedCrossRefGoogle Scholar
  40. 40.
    Amrutkar, D.V., K.B. Ploug, A. Hay-Schmidt, F. Porreca, J. Olesen, and I. Jansen-Olesen. 2012. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system. Pain 153: 830–838.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Puledda, F., R. Messina, and P.J. Goadsby. 2017. An update on migraine: current understanding and future directions. Journal of Neurology 264: 2031–2039.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Antonaci, F., N. Ghiotto, S. Wu, et al. 2016. Recent advances in migraine therapy. Springerplus 5: 637.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    El Gazzar, M.A., R. El Mezayen, M.R. Nicolls, et al. 2007. Thymoquinone attenuates proinflammatory responses in lipopolysaccharide-activated mast cells by modulating NF-kappaB nuclear transactivation. Biochimica et Biophysica Acta 1770: 556–564.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Strecker, T., M. Dux, and K. Messlinger. 2002. Nitric oxide releases calcitonin-gene-related peptide from rat dura mater encephali promoting increases in meningeal blood flow. Journal of Vascular Research 39: 489–496.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Theoharides, T.C., P. Valent, and C. Akin. 2015. Mast cells, mastocytosis, and related disorders. The New England Journal of Medicine 373: 163–172.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Physiology, Faculty of MedicineAbant Izzet Baysal UniversityBoluTurkey
  2. 2.Department of Physiology, Faculty of MedicineBiruni UniversityIstanbulTurkey
  3. 3.Department of Neurosurgery, Faculty of MedicineAbant Izzet Baysal UniversityBoluTurkey
  4. 4.Department of Medical Biochemistry, Faculty of MedicineAbant Izzet Baysal UniversityBoluTurkey

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