Effects of esculetin on pain behavior and mechanisms underlying migraine pain in in-vivo and ex-vivo rat models of migraine

This study aimed to investigate the effects of Esculetin, one of the coumarin derivatives, on migraine-related markers in in-vivo and ex-vivo migraine models induced by nitroglycerin (NTG) in rats. In the in-vivo experiments, Wistar male rats were divided into 7 groups (n=7/group). The migraine model was established by 10 mg/kg NTG administration. Different doses of Esculetin (5, 10, and 20 mg/kg) was tested in the migraine model and migraine drug sumatriptan was administered as a positive control group. The effect of Esculetin alone was also tested. In ex-vivo trigeminovascular preparations (n=8/group), the effect of Esculetin (100 μΜ) on the release of calcitonin gene-related peptide (CGRP) induced by NTG. Mechanical hyperalgesia was assessed by von-Frey filaments and CGRP concentrations in in-vivo and ex-vivo samples and c-Fos expression in brainstem by ELISA and meningeal mast cells by toluidine-blue staining. Data were compared by one-way ANOVA. In the in-vivo experiments, Esculetin reduced the hyperalgesia, plasma and trigeminal ganglion CGRP levels, brainstem CGRP and c-fos levels, and mast cell activation induced by NTG (p<0.05). In the ex-vivo trigeminal ganglion and brainstem preparations, Esculetin reduced CGRP release stimulated by NTG (p<0.001), but it was ineffective in dural preparations. Sumatriptan, as a positive control, reversed the effects of NTG in in-vivo and ex-vivo experiments (p<0.01). The fact that Esculetin reduced the release of migraine mediator CGRP from migraine pain-related structures in the in-vivo and ex-vivo and suppressed meningeal mast cell activation, which is a key component of neurogenic inflammation, suggests that it may be a new multi-targeted drug candidate in the treatment of migraine. Future studies with different migraine models and clinical trials will contribute to further understanding the anti-migraine potential of Esculetin