Proefschrift Kayi Chan

Neurovascular pharmacology of prospective antimigraine drugs

In this dissertation, neurovascular effect of several prospective antimigraine drugs are pharmacologically described.

Currently available drugs for the acute treatment of migraine, i.e. ergot alkaloids and triptans, are cranial vasoconstrictors. Although cranial vasoconstriction is likely to mediate ‑at least a part of- their therapeutic effects, this property also causes vascular side effects. In view of these limitations, novel antimigraine drugs devoid of vascular (side) effects are being explored. Calcitonin gene-related peptide (CGRP) receptor antagonists, which do not have direct vasoconstrictor effects, are under development. Other classes of drugs, such as glutamate receptor antagonists, VIP and PACAP receptor antagonists have also been proposed as potential targets for acute antimigraine drugs.

Although these prospective drugs do not directly induce vasoconstriction, they may well induce indirect vascular effects by inhibiting or modulating responses to endogenous vasoactive substances. We have investigated the vascular effects of the CGRP receptor antagonist, telcagepant, and the VIP and PACAP receptor antagonists, in a human ex vivo model as well as the neurovascular effects of several glutamate receptor type antagonists in a rat in vivo model. The data suggest that most of these antagonists have indirect effects on the vascular tone. These indirect vascular effects might contribute to the therapeutic efficacy of these compounds, but may alternatively also lead to vascular side effects.