Migraine: focus on calcitonin gene-related peptide (CGRP)

Principal investigator: Dr. Antoinette Maassen van den Brink, Associate Professor

Migraine is a neurovascular disorder, which has been ranked by the WHO as the 7th highest cause of disability in the world. Our laboratory is one of the leaders in neurovascular research on the pathophysiology and pharmacological treatment of migraine. We focus both on the therapeutic efficacy and the cardiovascular side effect profile of the drugs. In the past we have performed landmark studies in relation to the triptans (i.e., 5 HT1B/1D receptor agonists), including pharmacogenetic trials.1-3 We are currently involved in the investigation of CGRP-ergic ligands in relation to antimigraine treatment.4,5

Future antimigraine drugs are likely to be antibodies against CGRP or the CGRP receptor. In addition, glutamatergic ligands,6,7 novel formulations of 'older' antimigraine drugs,8 as well as many other targets9 are being explored. It is important to assess the potential cardiovascular effects of future drugs, since these may be clinically relevant, even for drugs that are primarily thought to act via a neuronal mechanism of action.7,9 We have an outstanding track record on preclinical neurovascular studies, in vivo as well as in vitro, on both human tissues and animals.

State-of-the-art techniques to evaluate (neuro)vascular function in vivo (telemetry, metabolic cages, ultrasound, laser Doppler flow, microCT imaging, intravital microscopy) and ex vivo (Langendorff heart preparation, Mulvany myograph), combined with a full range of biochemical and molecular-biological analyses, including epigenetic techniques,10 are available. In addition, we have access to human coronary and meningeal arteries. Recently, we have developed several models to assess trigeminovascular activity in vivo in humans. These methods include saliva measurements of CGRP under different experimental conditions,11 but also a model where trigeminal CGRP release is assessed with laser Doppler technology.12 This model can be applied to study pathophysiological mechanisms,13 but together with medical doctors from our institute we are also able to perform detailed pharmacodynamic and pharmacokinetic studies on the effects of prospective antimigraine drugs in humans.

Companies we collaborate with:

  • Allergan
  • Johnson & Johnson
  • Eli Lilly and Company
  • MAP Pharmaceuticals
  • Novartis
  • Tonix Pharmaceuticals
  • Unilever

  • References
    1. Maassen van den Brink A, Reekers M, Bax WA, Ferrari MD, Saxena PR. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation 1998;98:25-30.

    2. Mehrotra S, Vanmolkot KR, Frants RR, van den Maagdenberg AM, Ferrari MD, Maassen van den Brink A. The phe-124-Cys and A-161T variants of the human 5-HT1B receptor gene are not major determinants of the clinical response to sumatriptan. Headache 2007;47:711-716.

    3. Chan KY, Labruijere S, Ramirez Rosas MB, de Vries R, Garrelds IM, Danser AHJ, Villalon CM, van den Bogaerdt A, Dirven C, Maassen van den Brink A. Cranioselectivity of Sumatriptan Revisited: Pronounced Contractions to Sumatriptan in Small Human Isolated Coronary Artery. CNS Drugs 2014;28:273-278.

    4. Chan KY, Edvinsson L, Eftekhari S, Kimblad PO, Kane SA, Lynch J, Hargreaves RJ, de Vries R, Garrelds IM, van den Bogaerdt AJ, Danser AHJ, Maassen van den Brink A. Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries. J Pharmacol Exp Ther 2010;334:746-752.

    5. Edvinsson L, Chan KY, Eftekhari S, Nilsson E, de Vries R, Saveland H, Dirven CM, Danser AHJ, Maassen van den Brink A. Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries. Cephalalgia 2010;30:1233-1240.

    6. Chan K, Maassen van den Brink A. Glutamate receptor antagonists in the management of migraine. Drugs 2014;74:1165-1176.

    7. Chan KY, Gupta S, de Vries R, Danser AHJ, Villalon CM, Munoz-Islas E, Maassen van den Brink A. Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model. Br J Pharmacol 2010;160:1316-1325.

    8. Labruijere S, Chan KY, de Vries R, van den Bogaerdt AJ, Dirven CM, Danser AHJ, Kori SH, Maassen van den Brink A. Dihydroergotamine and sumatriptan in isolated human coronary artery, middle meningeal artery and saphenous vein. Cephalalgia 2015; In Press.

    9. Chan KY, Vermeersch S, de Hoon J, Villalon CM, Maassen van den Brink A. Potential mechanisms of prospective antimigraine drugs: a focus on vascular (side) effects. Pharmacol Ther 2011;129:332-351.

    10. Labruijere S, Stolk L, Verbiest M, de Vries R, Garrelds IM, Eilers PH, Danser AHJ, Uitterlinden AG, Maassen van den Brink A. Methylation of migraine-related genes in different tissues of the rat. PLoS One 2014;9:e87616.

    11. van Oosterhout WPJ, Schoonman GG, Garrelds IM, Danser AHJ, Chan KY, Terwindt GM, Ferrari MD, Maassen van den Brink A. A human capsaicin model to quantitatively assess salivary CGRP secretion. Cephalalgia 2015;In Press.

    12. Ibrahimi K, Vermeersch S, Danser AHJ, Villalon C, van den Meiracker A, de Hoon J, Maassen van den Brink A. Development of an experimental model to study trigeminal nerve-mediated vasodilation on the human forehead. Cephalalgia 2014;34:514-522.

    13. Ibrahimi K, van Oosterhout WPJ, van Dorp W, Danser AHJ, Garrelds IM, Kushner SA, Lesaffre EMEH, Terwindt GM, Ferrari MD, van den Meiracker AH, Maassen van den Brink A. Reduced trigeminovascular cyclicity in patients with menstrually-related migraine. Neurology 2015; 84:125-131.