Charlotte Ernstsen, Karina Obelitz-Ryom, David Møbjerg B Kristensen, Jes Olesen, Sarah Louise Christensen, Song Guo
{"title":"GTN 诱导偏头痛的机制:偏头痛相关小鼠模型中 NOS 同工酶、sGC 和过氧亚硝酸盐的作用。","authors":"Charlotte Ernstsen, Karina Obelitz-Ryom, David Møbjerg B Kristensen, Jes Olesen, Sarah Louise Christensen, Song Guo","doi":"10.1177/03331024241277542","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Migraine research has highlighted the pivotal role of nitric oxide (NO) in migraine pathophysiology. Nitric oxide donors such as glyceryl trinitrate (GTN) induce migraine attacks in humans, whereas spontaneous migraine attacks can be aborted by inhibiting NO production. The present study aimed to investigate how GTN triggers migraine through its three nitric oxide synthase (NOS) isoforms (neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)) via a suspected feed-forward phenomenon.</p><p><strong>Methods: </strong>Migraine-relevant hypersensitivity was induced by repeated injection of GTN in an <i>in vivo</i> mouse model. Cutaneous tactile sensitivity was assessed using von Frey filaments. Signaling pathways involved in this model were dissected using non-selective and selective NOS inhibitors, knockout mice lacking eNOS or nNOS and their wild-type control mice. Also, we tested a soluble guanylate cyclase inhibitor and a peroxynitrite decomposition catalyst (N<sub>total </sub>= 312).</p><p><strong>Results: </strong>Non-selective NOS inhibition blocked GTN-induced hypersensitivity. This response was partially associated with iNOS, and potentially nNOS and eNOS conjointly. Furthermore, we found that the GTN response was largely dependent on the generation of peroxynitrite and partly soluble guanylate cyclase.</p><p><strong>Conclusions: </strong>Migraine-relevant hypersensitivity induced by GTN is mediated by a possible feed-forward phenomenon of NO driven mainly by iNOS but with contributions from other isoforms. The involvement of peroxynitrite adds to the notion that oxidative stress reactions are also involved.</p>","PeriodicalId":10075,"journal":{"name":"Cephalalgia","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mechanisms of GTN-induced migraine: Role of NOS isoforms, sGC and peroxynitrite in a migraine relevant mouse model.\",\"authors\":\"Charlotte Ernstsen, Karina Obelitz-Ryom, David Møbjerg B Kristensen, Jes Olesen, Sarah Louise Christensen, Song Guo\",\"doi\":\"10.1177/03331024241277542\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Migraine research has highlighted the pivotal role of nitric oxide (NO) in migraine pathophysiology. Nitric oxide donors such as glyceryl trinitrate (GTN) induce migraine attacks in humans, whereas spontaneous migraine attacks can be aborted by inhibiting NO production. The present study aimed to investigate how GTN triggers migraine through its three nitric oxide synthase (NOS) isoforms (neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)) via a suspected feed-forward phenomenon.</p><p><strong>Methods: </strong>Migraine-relevant hypersensitivity was induced by repeated injection of GTN in an <i>in vivo</i> mouse model. Cutaneous tactile sensitivity was assessed using von Frey filaments. Signaling pathways involved in this model were dissected using non-selective and selective NOS inhibitors, knockout mice lacking eNOS or nNOS and their wild-type control mice. Also, we tested a soluble guanylate cyclase inhibitor and a peroxynitrite decomposition catalyst (N<sub>total </sub>= 312).</p><p><strong>Results: </strong>Non-selective NOS inhibition blocked GTN-induced hypersensitivity. This response was partially associated with iNOS, and potentially nNOS and eNOS conjointly. Furthermore, we found that the GTN response was largely dependent on the generation of peroxynitrite and partly soluble guanylate cyclase.</p><p><strong>Conclusions: </strong>Migraine-relevant hypersensitivity induced by GTN is mediated by a possible feed-forward phenomenon of NO driven mainly by iNOS but with contributions from other isoforms. The involvement of peroxynitrite adds to the notion that oxidative stress reactions are also involved.</p>\",\"PeriodicalId\":10075,\"journal\":{\"name\":\"Cephalalgia\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.0000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cephalalgia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/03331024241277542\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cephalalgia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/03331024241277542","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景:偏头痛研究强调了一氧化氮(NO)在偏头痛病理生理学中的关键作用。一氧化氮供体(如三硝酸甘油酯(GTN))可诱发偏头痛发作,而抑制一氧化氮的产生则可中止偏头痛的自发发作。本研究旨在探讨GTN如何通过其三种一氧化氮合酶(NOS)同工酶(神经元NOS(nNOS)、内皮NOS(eNOS)和诱导型NOS(iNOS))通过一种疑似前馈现象诱发偏头痛:方法:在小鼠体内模型中重复注射 GTN,诱导偏头痛相关超敏反应。使用 von Frey 灯丝评估皮肤触觉敏感性。利用非选择性和选择性 NOS 抑制剂、缺乏 eNOS 或 nNOS 的基因敲除小鼠及其野生型对照小鼠,对该模型中涉及的信号通路进行了剖析。此外,我们还测试了一种可溶性鸟苷酸环化酶抑制剂和一种过氧化亚硝酸盐分解催化剂(Ntotal = 312):结果:非选择性 NOS 抑制阻断了 GTN 诱导的超敏反应。这种反应部分与 iNOS 有关,也可能与 nNOS 和 eNOS 共同有关。此外,我们还发现 GTN 反应在很大程度上依赖于过氧化亚硝酸盐的生成,部分依赖于可溶性鸟苷酸环化酶:结论:GTN诱导的偏头痛相关超敏反应可能是由主要由iNOS驱动的NO前馈现象介导的,但也有其他同工酶的贡献。过氧化亚硝酸盐的参与增加了氧化应激反应也参与其中的概念。
Mechanisms of GTN-induced migraine: Role of NOS isoforms, sGC and peroxynitrite in a migraine relevant mouse model.
Background: Migraine research has highlighted the pivotal role of nitric oxide (NO) in migraine pathophysiology. Nitric oxide donors such as glyceryl trinitrate (GTN) induce migraine attacks in humans, whereas spontaneous migraine attacks can be aborted by inhibiting NO production. The present study aimed to investigate how GTN triggers migraine through its three nitric oxide synthase (NOS) isoforms (neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)) via a suspected feed-forward phenomenon.
Methods: Migraine-relevant hypersensitivity was induced by repeated injection of GTN in an in vivo mouse model. Cutaneous tactile sensitivity was assessed using von Frey filaments. Signaling pathways involved in this model were dissected using non-selective and selective NOS inhibitors, knockout mice lacking eNOS or nNOS and their wild-type control mice. Also, we tested a soluble guanylate cyclase inhibitor and a peroxynitrite decomposition catalyst (Ntotal = 312).
Results: Non-selective NOS inhibition blocked GTN-induced hypersensitivity. This response was partially associated with iNOS, and potentially nNOS and eNOS conjointly. Furthermore, we found that the GTN response was largely dependent on the generation of peroxynitrite and partly soluble guanylate cyclase.
Conclusions: Migraine-relevant hypersensitivity induced by GTN is mediated by a possible feed-forward phenomenon of NO driven mainly by iNOS but with contributions from other isoforms. The involvement of peroxynitrite adds to the notion that oxidative stress reactions are also involved.
期刊介绍:
Cephalalgia contains original peer reviewed papers on all aspects of headache. The journal provides an international forum for original research papers, review articles and short communications. Published monthly on behalf of the International Headache Society, Cephalalgia''s rapid review averages 5 ½ weeks from author submission to first decision.