Trigeminovascular calcitonin gene-related peptide function in Cacna1a R192Q-mutated knock-in mice
Familial hemiplegic migraine type 1 (FHM1) is a rare migraine subtype. Whereas transgenic knock-in mice with the human pathogenic FHM1 R192Q missense mutation in the Cacna1a gene reveal overall neuronal hyperexcitability, the effects on the trigeminovascular system and calcitonin gene-related peptide (CGRP) receptor are largely unknown. This gains relevance as blockade of CGRP and its receptor are therapeutic targets under development. Hence, we set out to test these effects in FHM1 mice. We characterized the trigeminovascular system of wild-type and FHM1 mice through: (i) in vivo capsaicin- and CGRP-induced dural vasodilation in a closed-cranial window; (ii) ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion and trigeminal nucleus caudalis; and (iii) peripheral vascular function in vitro. In mutant mice, dural vasodilatory responses were significantly decreased compared to controls. The ex vivo release of CGRP was not different in the components of the trigeminovascular system between genotypes; however, sumatriptan diminished the release in the trigeminal ganglion, trigeminal nucleus caudalis and dura mater but only in wild-type mice. Peripheral vascular function was similar between genotypes. These data suggest that the R192Q mutation might be associated with trigeminovascular CGRP receptor desensitization. Novel antimigraine drugs should be able to revert this complex phenomenon.
|Calcitonin gene-related peptide, migraine, R192Q, trigeminovascular, vasodilation|
|Journal of Cerebral Blood Flow and Metabolism|
|This work was funded by the European Commission 7th Framework Programme; grant id fp7/602633 - Mechanisms and Treatment of Migraine and its Chronification (EUROHEADPAIN)|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Chan, K.Y, Labastida-Ramirez, A, Ramírez-Rosas, M.B, Labruijere, S, Garrelds, I.M, Danser, A.H.J, … Maassen van den Brink, A. (2017). Trigeminovascular calcitonin gene-related peptide function in Cacna1a R192Q-mutated knock-in mice. Journal of Cerebral Blood Flow and Metabolism. doi:10.1177/0271678X17725673