PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine
Résumé
Background Calcitonin gene‑related peptide (CGRP) antagonizing drugs represents the most important advance in
migraine therapy for decades. However, these new drugs are only effective in 50–60% of patients. Recent studies have
shown that the pituitary adenylate cyclase‑activating peptide (PACAP38) pathway is independent from the CGRP
signaling pathway. Here, we investigate PACAP38 signaling pathways in relation to glyceryl trinitrate (GTN), levcro‑
makalim and sumatriptan.
Methods In vivo mouse models of PACAP38‑, GTN‑, and levcromakalim‑induced migraine were applied using tactile
sensitivity to von Frey filaments as measuring readout. Signaling pathways involved in the three models were dis‑
sected using PACAP‑inhibiting antibodies (mAbs) and sumatriptan.
Results We showed that PACAP mAbs block PACAP38 induced hypersensitivity, but not via signaling pathways
involved in GTN and levcromakalim. Also, sumatriptan has no effect on PACAP38‑induced hypersensitivity relevant
to migraine. This is the first study testing the effect of a PACAP‑inhibiting drug on GTN‑ and levcromakalim‑induced
hypersensitivity.
Conclusions Based on the findings in our mouse model of migraine using migraine‑inducing compounds and
anti‑migraine drugs, we suggest that PACAP acts via a distinct pathway. Using PACAP38 antagonism may be a novel
therapeutic target of interest in a subgroup of migraine patients who do not respond to existing therapies.
Domaines
Sciences du Vivant [q-bio]
Origine : Fichiers éditeurs autorisés sur une archive ouverte