Esculetin attenuates migraine-like pain via CGRP suppression and meningeal mast cell modulation in rat models

Ayca Nur GONUL; Ibrahim Ethem TORUN; Yasemin Baranoglu KILINC; Erkan KILINC

doi:10.1631/jzus.B2500147

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Esculetin attenuates migraine-like pain via CGRP suppression and meningeal mast cell modulation in rat models

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Research Article | Updated：2026-06-23

Esculetin attenuates migraine-like pain via CGRP suppression and meningeal mast cell modulation in rat models
Esculetin attenuates migraine-like pain via CGRP suppression and meningeal mast cell modulation in rat models
秦皮乙素可通过抑制降钙素基因相关肽（CGRP）和调节脑膜肥大细胞减轻大鼠偏头痛样疼痛
Journal of Zhejiang University-SCIENCE B Vol. 27, Issue 6, Pages: 615-627(2026)
Affiliations：

1.Department of Physiology, Faculty of Medicine, Bolu Abant Izzet Baysal University, Bolu 14030, Türkiye
2.Department of Pediatrics, Faculty of Medicine, Bolu Abant Izzet Baysal University, Bolu 14030, Türkiye
3.Department of Physiology, Cerrahpasa Faculty of Medicine, İstanbul University-Cerrahpaşa, İstanbul 34098, Türkiye
Funds：
DOI：10.1631/jzus.B2500147
CLC：
CSTR：
Received：26 March 2025，

Revised：2025-09-01，

Online First：01 May 2026，

Published：15 June 2026
Accepted：

Ayca Nur GONUL,Ibrahim Ethem TORUN,Yasemin Baranoglu KILINC等.秦皮乙素可通过抑制降钙素基因相关肽（CGRP）和调节脑膜肥大细胞减轻大鼠偏头痛样疼痛[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(06):615-627.

Ayca Nur GONUL, Ibrahim Ethem TORUN, Yasemin Baranoglu KILINC, et al. Esculetin attenuates migraine-like pain via CGRP suppression and meningeal mast cell modulation in rat models[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(6): 615-627.
Ayca Nur GONUL,Ibrahim Ethem TORUN,Yasemin Baranoglu KILINC等.秦皮乙素可通过抑制降钙素基因相关肽（CGRP）和调节脑膜肥大细胞减轻大鼠偏头痛样疼痛[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(06):615-627. DOI： 10.1631/jzus.B2500147.

Ayca Nur GONUL, Ibrahim Ethem TORUN, Yasemin Baranoglu KILINC, et al. Esculetin attenuates migraine-like pain via CGRP suppression and meningeal mast cell modulation in rat models[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(6): 615-627. DOI： 10.1631/jzus.B2500147.

摘要

越来越多的证据表明，秦皮乙素作为一种5-脂氧合酶抑制剂，因其具有强效抗炎、抗伤害感受及γ-氨基丁酸A型（GABA

）受体部分激动活性等多种药理学特性，而显示出药物治疗潜力。然而，其对偏头痛的治疗效果仍有待探索。因此，本研究探讨了秦皮乙素在大鼠偏头痛样状态下相关机制的影响。通过体内实验测试了三种不同剂量（5、10和20 mg/kg）的秦皮乙素在硝酸甘油（NTG）诱导的偏头痛模型中的全身性效应；同时，通过体外实验检测了其对三叉神经血管系统关键结构（三叉神经节、三叉神经核以及脑膜传入神经）释放降钙素基因相关肽（CGRP）的直接作用。两组实验均以舒马普坦为阳性对照。体内实验结果显示，秦皮乙素减轻了NTG诱导的机械性痛觉过敏，降低了三叉神经CGRP和c-Fos表达水平，并减少了脑膜肥大细胞脱颗粒和数量；体外实验表明，秦皮乙素能抑制NTG刺激下的三叉神经血管组织块（脑膜组织块除外）的CGRP释放。舒马普坦可逆转两组实验中NTG诱发的变化。综上所述，秦皮乙素能抗伤害感受活性，降低三叉神经血管的CGRP浓度，并减轻脑膜肥大细胞的脱颗粒，因此可作为一种缓解偏头痛的治疗选择，但仍需进一步研究来加以证实。

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 γ-aminobutyric acid type A (GABA

) 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

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.

关键词

Keywords

references

Baranoglu Kilinc Y , Torun IE , Kilinc E , 2024 . D2 dopamine receptor-mediated mechanisms of dopaminergic system modulation in in vivo and in vitro experimental models of migraine . Eur J Neurosci , 59 ( 6 ): 1177 - 1193 . https://doi.org/10.1111/ejn.16106 https://doi.org/10.1111/ejn.16106

Bolay H , Reuter U , Dunn AK , et al. , 2002 . Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model . Nat Med , 8 ( 2 ): 136 - 142 . https://doi.org/10.1038/nm0202-136 https://doi.org/10.1038/nm0202-136

Cetinkaya A , Kilinc E , Camsari C , et al. , 2020 . Effects of estrogen and progesterone on the neurogenic inflammatory neuropeptides: implications for gender differences in migraine . Exp Brain Res , 238 ( 11 ): 2625 - 2639 . https://doi.org/10.1007/s00221-020-05923-7 https://doi.org/10.1007/s00221-020-05923-7

Cheng YJ , Tian XL , Zeng YZ , et al. , 2021 . Esculetin protects against early sepsis via attenuating inflammation by inhibiting NF- κ B and STAT1/STAT3 signaling . Chin J Nat Med , 19 ( 6 ): 432 - 441 . https://doi.org/10.1016/S1875-5364(21)60042-0 https://doi.org/10.1016/S1875-5364(21)60042-0

Citak A , Kilinc E , Torun IE , et al. , 2022 . The effects of certain TRP channels and voltage-gated KCNQ/Kv7 channel opener retigabine on calcitonin gene-related peptide release in the trigeminovascular system . Cephalalgia , 42 ( 13 ): 1375 - 1386 . https://doi.org/10.1177/03331024221114773 https://doi.org/10.1177/03331024221114773

Danis A , Baranoglu Kilinc Y , Torun IE , et al. , 2023 . Esculetin alleviates pentylenetetrazole-induced seizures, cognitive impairment and pro-inflammatory cytokines and suppresses penicillin-induced epileptiform activity in rats . Life Sci , 313 : 121300 . https://doi.org/10.1016/j.lfs.2022.121300 https://doi.org/10.1016/j.lfs.2022.121300

Frederiksen SD , Bekker-Nielsen Dunbar M , Snoer AH , et al. , 2020 . Serotonin and neuropeptides in blood from episodic and chronic migraine and cluster headache patients in case-control and case-crossover settings: a systematic review and meta-analysis . Headache , 60 ( 6 ): 1132 - 1164 . https://doi.org/10.1111/head.13802 https://doi.org/10.1111/head.13802

Giménez-Bastida JA , González-Sarrías A , Laparra-Llopis JM , et al. , 2021 . Targeting mammalian 5-lipoxygenase by dietary phenolics as an anti-inflammatory mechanism: a systematic review . Int J Mol Sci , 22 ( 15 ): 7937 . https://doi.org/10.3390/ijms22157937 https://doi.org/10.3390/ijms22157937

Jeong NH , Yang EJ , Jin ML , et al. , 2018 . Esculetin from Fraxinus rhynchophylla attenuates atopic skin inflammation by inhibiting the expression of inflammatory cytokines . Int Immunopharmacol , 59 : 209 - 216 . https://doi.org/10.1016/j.intimp.2018.04.005 https://doi.org/10.1016/j.intimp.2018.04.005

Kilinc E , Dagistan Y , Kotan B , et al. , 2017a . Effects of Nigella sativa seeds and certain species of fungi extracts on number and activation of dural mast cells in rats . Physiol Int , 104 ( 1 ): 15 - 24 . https://doi.org/10.1556/2060.104.2017.1.8 https://doi.org/10.1556/2060.104.2017.1.8

Kilinc E , Guerrero-Toro C , Zakharov A , et al. , 2017b . Serotonergic mechanisms of trigeminal meningeal nociception: implications for migraine pain . Neuropharmacology , 116 : 160 - 173 . https://doi.org/10.1016/j.neuropharm.2016.12.024 https://doi.org/10.1016/j.neuropharm.2016.12.024

Kilinc E , Dagistan Y , Kukner A , et al. , 2018 . Salmon calcitonin ameliorates migraine pain through modulation of CGRP release and dural mast cell degranulation in rats . Clin Exp Pharmacol Physiol , 45 ( 6 ): 536 - 546 . https://doi.org/10.1111/1440-1681.12915 https://doi.org/10.1111/1440-1681.12915

Kilinc E , Tore F , Dagistan Y , et al. , 2020 . Thymoquinone inhibits neurogenic inflammation underlying migraine through modulation of calcitonin gene-related peptide release and stabilization of meningeal mast cells in glyceryltrinitrate-induced migraine model in rats . Inflammation , 43 : 264 - 273 . https://doi.org/10.1007/s10753-019-01115-w https://doi.org/10.1007/s10753-019-01115-w

Kilinc E , Ankarali S , Torun IE , et al. , 2022 . Receptor mechanisms mediating the anti-neuroinflammatory effects of endocannabinoid system modulation in a rat model of migraine . Eur J Neurosci , 55 ( 4 ): 1015 - 1031 . https://doi.org/10.1111/ejn.14897 https://doi.org/10.1111/ejn.14897

Kilinc E , Torun IE , Baranoglu Kilinc Y , 2024 . Meningeal mast cell-mediated mechanisms of cholinergic system modulation in neurogenic inflammation underlying the pathophysiology of migraine . Eur J Neurosci , 59 ( 9 ): 2181 - 2192 . https://doi.org/10.1111/ejn.15888 https://doi.org/10.1111/ejn.15888

Kilinc YB , Kilinc E , Danis A , et al. , 2023 . Mitochondrial metabolism related markers GDF-15, FGF-21, and HIF-1α are elevated in pediatric migraine attacks . Headache , 63 ( 8 ): 1076 - 1086 . https://doi.org/10.1111/head.14618 https://doi.org/10.1111/head.14618

Kim D , Jeong S , Lee S , et al. , 2025 . Esculetin inhibits mast cell-mediated allergic inflammation and anaphylaxis by suppressing the FcɛRI signaling pathway (Abstract ID: 162178) . J Pharmacol Exp Ther , 392 ( S3 ): 100683 . https://doi.org/10.1016/j.jpet.2024.100683 https://doi.org/10.1016/j.jpet.2024.100683

Koyuncu Irmak D , Kilinc E , Tore F , 2019 . Shared fate of meningeal mast cells and sensory neurons in migraine . Front Cell Neurosci , 13 : 136 . https://doi.org/10.3389/fncel.2019.00136 https://doi.org/10.3389/fncel.2019.00136

Labastida-Ramírez A , Rubio-Beltrán E , Villalón CM , et al. , 2019 . Gender aspects of CGRP in migraine . Cephalalgia , 39 ( 3 ): 435 - 444 . https://doi.org/10.1177/0333102417739584 https://doi.org/10.1177/0333102417739584

Labastida-Ramírez A , Caronna E , Gollion C , et al. , 2023 . Mode and site of action of therapies targeting CGRP signaling . J Headache Pain , 24 : 125 . https://doi.org/10.1186/s10194-023-01644-8 https://doi.org/10.1186/s10194-023-01644-8

Lee CR , Shin EJ , Kim HC , et al. , 2011 . Esculetin inhibits N -methyl- d -aspartate neurotoxicity via glutathione preservation in primary cortical cultures . Lab Anim Res , 27 ( 3 ): 259 - 263 . https://doi.org/10.5625/lar.2011.27.3.259 https://doi.org/10.5625/lar.2011.27.3.259

Levy D , Moskowitz MA , 2023 . Meningeal mechanisms and the migraine connection . Annu Rev Neurosci , 46 : 39 - 58 . https://doi.org/10.1146/annurev-neuro-080422-105509 https://doi.org/10.1146/annurev-neuro-080422-105509

Liang CY , Ju WH , Pei SM , et al. , 2017 . Pharmacological activities and synthesis of esculetin and its derivatives: a mini-review . Molecules , 22 ( 3 ): 387 . https://doi.org/10.3390/molecules22030387 https://doi.org/10.3390/molecules22030387

Neichi T , Koshihara Y , Murota SI , 1983 . Inhibitory effect of esculetin on 5-lipoxygenase and leukotriene biosynthesis . Biochim Biophys Acta , 753 ( 1 ): 130 - 132 . https://doi.org/10.1016/0005-2760(83)90106-6 https://doi.org/10.1016/0005-2760(83)90106-6

Okubo M , Yamanaka H , Kobayashi K , et al. , 2010 . Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal cord contribute to the generation of neuropathic pain . Glia , 58 ( 5 ): 599 - 610 . https://doi.org/10.1002/glia.20948 https://doi.org/10.1002/glia.20948

Ottosson A , Edvinsson L , 1997 . Release of histamine from dural mast cells by substance P and calcitonin gene-related peptide . Cephalalgia , 17 ( 3 ): 166 - 174 . https://doi.org/10.1046/j.1468-2982.1997.1703166.x https://doi.org/10.1046/j.1468-2982.1997.1703166.x

Ramachandran R , 2018 . Neurogenic inflammation and its role in migraine . Semin Immunopathol , 40 ( 3 ): 301 - 314 . https://doi.org/10.1007/s00281-018-0676-y https://doi.org/10.1007/s00281-018-0676-y

Ramachandran R , Bhatt DK , Ploug KB , et al. , 2014 . Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation . Cephalalgia , 34 ( 2 ): 136 - 147 . https://doi.org/10.1177/0333102413502735 https://doi.org/10.1177/0333102413502735

Rasmussen RH , Jansen-Olesen I , Kristensen DM , et al. , 2022 . Ex vivo release of calcitonin gene-related peptide from the trigeminovascular system in rodents . J Vis Exp , 183 : e63723 . https://doi.org/10.3791/63723 https://doi.org/10.3791/63723

Rzodkiewicz P , Gasinska E , Maslinski S , et al. , 2015 . Antinociceptive properties of esculetin in non-inflammatory and inflammatory models of pain in rats . Clin Exp Pharmacol Physiol , 42 ( 2 ): 213 - 219 . https://doi.org/10.1111/1440-1681.12346 https://doi.org/10.1111/1440-1681.12346

Rzodkiewicz P , Gąsińska E , Gajewski M , et al. , 2016 . Esculetin reduces leukotriene B4 level in plasma of rats with adjuvant-induced arthritis . Reumatologia , 54 ( 4 ): 161 - 164 . https://doi.org/10.5114/reum.2016.62469 https://doi.org/10.5114/reum.2016.62469

Silvestro M , Orologio I , Siciliano M , et al. , 2023 . Emerging drugs for the preventive treatment of migraine: a review of CGRP monoclonal antibodies and gepants trials . Expert Opin Emerg Drugs , 28 ( 2 ): 79 - 96 . https://doi.org/10.1080/14728214.2023.2207819 https://doi.org/10.1080/14728214.2023.2207819

Singh L , Kaur A , Garg S , et al. , 2020 . Protective effect of esculetin, natural coumarin in mice model of fibromyalgia: targeting pro-inflammatory cytokines and MAO-A . Neurochem Res , 45 ( 10 ): 2364 - 2374 . https://doi.org/10.1007/s11064-020-03095-y https://doi.org/10.1007/s11064-020-03095-y

Singhuber J , Baburin I , Ecker GF , et al. , 2011 . Insights into structure-activity relationship of GABA A receptor modulating coumarins and furanocoumarins . Eur J Pharmacol , 668 ( 1-2 ): 57 - 64 . https://doi.org/10.1016/j.ejphar.2011.06.034 https://doi.org/10.1016/j.ejphar.2011.06.034

Skalicka-Woźniak K , Orhan IE , Cordell GA , et al. , 2016 . Implication of coumarins towards central nervous system disorders . Pharmacol Res , 103 : 188 - 203 . https://doi.org/10.1016/j.phrs.2015.11.023 https://doi.org/10.1016/j.phrs.2015.11.023

Sureda-Gibert P , Romero-Reyes M , Akerman S , 2022 . Nitroglycerin as a model of migraine: clinical and preclinical review . Neurobiol Pain , 12 : 100105 . https://doi.org/10.1016/j.ynpai.2022.100105 https://doi.org/10.1016/j.ynpai.2022.100105

Torun IE , Kilinc YB , Kilinc E , et al. , 2024 . TRESK channel activation ameliorates migraine-like pain via modulation of CGRP release from the trigeminovascular system and meningeal mast cells in experimental migraine models . Life Sci , 357 : 123091 . https://doi.org/10.1016/j.lfs.2024.123091 https://doi.org/10.1016/j.lfs.2024.123091

Woo TS , Yoon SY , Pena ICD , et al. , 2011 . Anticonvulsant effect of Artemisia capillaris Herba in mice . Biomol Ther , 19 ( 3 ): 342 - 347 . https://doi.org/10.4062/biomolther.2011.19.3.342 https://doi.org/10.4062/biomolther.2011.19.3.342

Wu KC , Chen YH , Cheng KS , et al. , 2013 . Suppression of voltage-gated Na + channels and neuronal excitability by imperatorin . Eur J Pharmacol , 721 ( 1-3 ): 49 - 55 . https://doi.org/10.1016/j.ejphar.2013.09.056 https://doi.org/10.1016/j.ejphar.2013.09.056

Yan J , Dussor G , 2014 . Ion channels and migraine . Headache , 54 ( 4 ): 619 - 639 . https://doi.org/10.1111/head.12323 https://doi.org/10.1111/head.12323

Zhang LL , Xie QX , Li XF , 2022 . Esculetin: a review of its pharmacology and pharmacokinetics . Phytother Res , 36 ( 1 ): 279 - 298 . https://doi.org/10.1002/ptr.7311 https://doi.org/10.1002/ptr.7311

Zhang WY , Mulatia S , Zhang MM , et al. , 2025 . Esculetin inhibited fever, pain, and inflammatory responses via binding to HSC70 . J Ethnopharmacol , 350 : 120022 . https://doi.org/10.1016/j.jep.2025.120022 https://doi.org/10.1016/j.jep.2025.120022

Zhu LP , Nang C , Luo F , et al. , 2016 . Esculetin attenuates lipopolysaccharide (LPS)-induced neuroinflammatory processes and depressive-like behavior in mice . Physiol Behav , 163 : 184 - 192 . https://doi.org/10.1016/j.physbeh.2016.04.051 https://doi.org/10.1016/j.physbeh.2016.04.051

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