Esculetin attenuates migraine-like pain via CGRP suppression and meningeal mast cell modulation in rat models
JOURNAL OF ZHEJIANG UNIVERSITY-SCIENCE B, vol.27, no.6, pp.615-627, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 27 Issue: 6
- Publication Date: 2026
- Doi Number: 10.1631/jzus.b2500147
- Journal Name: JOURNAL OF ZHEJIANG UNIVERSITY-SCIENCE B
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Aerospace Database, BIOSIS, EMBASE, MEDLINE, Zoological Record, Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Earth, Atmospheric, & Aquatic Science Collection (ProQuest), Health Research Premium Collection (ProQuest), Materials Science & Engineering Collection (ProQuest), Pharma Collection (ProQuest), Technology Collection (ProQuest)
- Page Numbers: pp.615-627
- Istanbul University Affiliated: No
Abstract
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 gamma-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. (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic) 5-(sic)(sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic) gamma-(sic)(sic)(sic)(sic) A (sic) (GABAA) (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic). (sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic). (sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic). (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic) (5, 10 (sic) 20 mg/kg) (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic) (NTG) (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic); (sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic) ((sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)) (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic) (CGRP) (sic)(sic)(sic)(sic)(sic). (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic). (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic) NTG (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic) CGRP (sic) c-Fos (sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic); (sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic) NTG (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic) ((sic)(sic)(sic)(sic)(sic)(sic)(sic)) (sic) CGRP (sic)(sic). (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic) NTG (sic)(sic)(sic)(sic)(sic). (sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic) CGRP (sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic), (sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic)(sic).