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 microg/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.
Juhl
Louise
L
Department of Neurology, Glostrup Research Institute, Glostrup Hospital, University of Copenhagen, DK-2600, Glostrup, Denmark. loujuh01@glo.regionh.dk
Edvinsson
Lars
L
Olesen
Jes
J
Jansen-Olesen
Inger
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004388:Dura Mater / Q000098:blood supply; D004558:Electric Stimulation; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects / Q000503:physiopathology; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000503:physiopathology; D008881:Migraine Disorders / Q000188:drug therapy; D009841:Oligonucleotides / Q000494:pharmacology*; D010841:Pia Mater / Q000098:blood supply; D011092:Polyethylene Glycols / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D052157:Aptamers, Nucleotide; C521401:NOX-C29; D009841:Oligonucleotides; D011092:Polyethylene Glycols; D015740:Calcitonin Gene-Related Peptide