摘要Growing evidence suggests that esculetin,a 5-lipoxygenase inhibitor,has pharmacotherapeutic potential due to its various pharmacological properties,such as potent anti-inflammatory,anti-nociceptive,and γ-aminobutyric acid type A(GABAA)receptor partial agonist activities.However,the effects of this promising agent on migraine remain unexplored.This study therefore examined the impact of esculetin on relevant mechanisms in migraine-like conditions in rats.The systemic effects of esculetin at three distinct doses(5,10,and 20 mg/kg)were tested in a nitroglycerin(NTG)-induced migraine model using in vivo experimental sets.The direct action of esculetin on the release of calcitonin gene-related peptide(CGRP)from critical structures of the trigeminovascular system(trigeminal ganglion,trigeminal nucleus,and meningeal afferents)was also tested in ex vivo experimental sets.Sumatriptan was used as a positive control in both sets of experiments.The in vivo results showed that esculetin reduced NTG-induced mechanical hyperalgesia and decreased trigeminal CGRP and cellular Fos proto-oncogene(c-Fos)levels.It also decreased degranulation and meningeal mast cell numbers.The ex vivo results revealed that esculetin reduced NTG-stimulated CGRP release from trigeminovascular explants,with the exception of meningeal explants.Sumatriptan reversed the NTG-induced changes in both experimental sets.Our findings suggest that esculetin exhibits anti-nociceptive activities in experimental migraine conditions,alleviating trigeminovascular CGRP concentrations and the degranulation of meningeal mast cells.Esculetin may thus represent a therapeutic option for relieving migraine headaches,although further research is needed to confirm this.