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
- 7 Downloads
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 WORDSNeurogenic inflammation Migraine Thymoquinone Meningeal mast cells CGRP
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.
- 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.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.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
- 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
- 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
- 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
- 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
- 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
- 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