Effect of two novel CGRP-binding compounds in a closed cranial window rat model

We investigated the in vivo effects of two novel calcitonin gene-related peptide (CGRP) binding molecules in the genuine closed cranial window model in the rat. The RNA-Spiegelmer (NOX-C89) and the monoclonal CGRP antibody are CGRP scavengers and might be used as an alternative to CGRP-receptor antagonists in the treatment of migraine. Rats were anaesthetized and a closed cranial window established. Changes in dural and pial artery diameter and mean arterial blood pressure were measured simultaneously. Infusion of the RNA-Spiegelmer or the CGRP antibody alone had no effect on the arteries or the mean arterial blood pressure. We then used a bolus of 0.3 μg/kg CGRP (n = 6) or electrical stimulation (25 V, 5 Hz, 1 ms pulse width and of 10 s of duration) (n = 6) to induce dilatation of dural and pial arteries (mediated via CGRP-receptors). Pre-treatment with the RNA-Spiegelmer inhibited CGRP-induced vasodilatation of the dural artery (from 38 ± 17% to 7 ± 3%) and the pial artery (from 14 ± 1% to 3 ± 2%) (P < 0.05). The RNA-Spiegelmer, however, did not significantly inhibit dilatation induced by electrical stimulation (P > 0.05). The CGRP antibody caused a significant reduction of the dural artery diameter caused by intravenous CGRP-infusion (from 23 ± 5% to 12 ± 3%) (P < 0.05), but did not inhibit dilatation caused by electrical stimulation (P > 0.05). In conclusion, the CGRP scavengers effectively inhibited the effect of circulating CGRP but do not modify the effect of electrical stimulation and the consequent liberation of CGRP from perivascular sensory nerve fibres.