CGRP function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat.
OBJECTIVE
Calcitonin gene-related peptide (CGRP) receptor antagonists effectively abort migraine headache and inhibit neurogenic vasodilatation in humans as well as rat models. Monoclonal antibodies typically have long half-lives, and we investigated whether or not function-blocking CGRP antibodies would inhibit neurogenic vasodilatation with a long duration of action and therefore be a possible approach to preventive therapy of migraine. During chronic treatment with anti-CGRP antibodies, we measured cardiovascular function, which might be a safety concern of CGRP inhibition.


METHODS
We used two rat blood flow models that measure electrically stimulated vasodilatation in the skin or in the middle meningeal artery (MMA). These vasomotor responses are largely dependent on the neurogenic release of CGRP from sensory afferents. To assess cardiovascular function during chronic systemic anti-CGRP antibody treatment, we measured heart rate and blood pressure in conscious rats.


RESULTS
Treatment with anti-CGRP antibodies inhibited skin vasodilatation or the increase in MMA diameter to a similar magnitude as treatment with CGRP receptor antagonists. Although CGRP antibody treatment had a slower onset of action than the CGRP receptor antagonists, the inhibition was still evident 1 week after dosing. Chronic treatment with anti-CGRP antibodies had no detectable effects on heart rate or blood pressure.


CONCLUSIONS
We showed for the first time that anti-CGRP antibodies exert a long lasting inhibition of neurogenic vasodilatation in two different rat models of arterial blood flow. We have provided strong preclinical evidence that anti-CGRP antibody may be a suitable drug candidate for the preventive treatment of migraine.
Zeller
J
J
Rinat Laboratories, Biotherapeutics and Bioinnovation Center, Pfizer Inc., South San Francisco, CA 94080, USA.
Poulsen
K T
KT
Sutton
J E
JE
Abdiche
Y N
YN
Collier
S
S
Chopra
R
R
Garcia
C A
CA
Pons
J
J
Rosenthal
A
A
Shelton
D L
DL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors* / Q000276:immunology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects / Q000378:metabolism; D008881:Migraine Disorders / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012867:Skin / Q000098:blood supply / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D015740:Calcitonin Gene-Related Peptide
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