Topiramate inhibits trigeminovascular activation: an intravital microscopy study.
Activation, or the altered perception of activation, of trigeminal nerves that innervate the cranial vasculature is considered to be a pivotal component of the pathophysiology of acute migraine. Calcitonin gene-related peptide (CGRP) levels are increased during migraine and after trigeminal nerve stimulation in the cat. Both CGRP and nitric oxide (NO) infusion causes headache and delayed migraine in migraineurs. Neurogenic stimulation of a cranial window, CGRP and NO injection all cause meningeal artery dilation in the rat when viewed using intravital microscopy. Topiramate is an antiepileptic drug with established efficacy as a migraine preventive, and has recently been shown to inhibit neurons of the trigeminocervical complex after superior sagittal sinus stimulation. In this study, we used intravital microscopy with neurogenic dural vasodilation, and CGRP- and NO-induced dilation to examine whether intravenous topiramate has effects on the trigeminovascular system. Topiramate was able to attentuate neurogenic dural vasodilation maximally after 15 min by 52% at 30 mg kg(-1) (t(5) = 6.78, n = 6); there was no significant inhibition at 10 mg kg(-1). There was also significant attenuation of the NO-induced dilation maximally after 15 min, at both 10 and 30 mg kg(-1) by 21% (t(6) = 6.09, n = 7) and 41% (t(6) = 5.3, n = 7), respectively. CGRP-induced dilation was not inhibited at either dose of topiramate. The study demonstrates that topiramate is likely to inhibit neurogenic dural vasodilation by inhibiting the release of CGRP from prejunctional trigeminal neurons, thus attenuating the dural vasodilation. Topiramate is not able to act postsynaptically at the blood vessels themselves as the CGRP-induced dilation was not attenuated. The data are consistent with an effect of topiramate on trigeminovascular activation which may form part of its preventive antimigraine mechanisms of action.
Headache Group, Institute of Neurology, London, UK.
Simon
S
Akerman
Peter J
PJ
Goadsby
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D004388:Dura Mater / Q000098:blood supply* / Q000187:drug effects* / Q000502:physiology; D004558:Electric Stimulation; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects / Q000502:physiology; D018715:Microscopy, Video; D009569:Nitric Oxide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077236:Topiramate; D014276:Trigeminal Nerve / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D000927:Anticonvulsants; D014665:Vasodilator Agents; D000077236:Topiramate; D005632:Fructose; D009569:Nitric Oxide; D015740:Calcitonin Gene-Related Peptide