Badaeva Anastasiia, Maiolino Luigi, Danilov Andrey, Naprienko Margarita, Danilov Alexey, Jacob Ursula M, Calabrese Vittorio
Department for Pathological Physiology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia.
Department of Medical, Surgical Advanced Technologies "G. F. Ingrassia", University of Catania, Catania, Italy.
Open Med (Wars). 2025 May 17;20(1):20251201. doi: 10.1515/med-2025-1201. eCollection 2025.
Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) are bioactive gasotransmitters implicated in migraine pathophysiology. These gases regulate vascular tone, nociceptive transmission, and inflammatory pathways, playing key roles in both the onset and modulation of migraine.
This review synthesizes current evidence on the role of NO, CO, and H₂S in migraine, focusing on their molecular mechanisms, interactions, and potential therapeutic implications. Data from human and animal studies were analyzed to elucidate their contributions to migraine pathogenesis.
NO is a well-established migraine trigger, with NO donors such as nitroglycerin inducing headache and migraine attacks via cyclic guanosine monophosphate (cGMP)-dependent pathways. CO interacts with NO and cGMP signaling in pain modulation, contributing to central and peripheral nociceptive processing. H₂S exerts dual effects: while its interaction with NO forms nitroxyl (HNO), activating transient receptor potential ankyrin 1 (TRPA1) channels and triggering calcitonin gene-related peptide (CGRP) release; it also demonstrates neuroprotective properties through antioxidant mechanisms and nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Additionally, epigenetic modifications of calcitonin gene-related peptide alpha (CALCA) have been implicated in migraine susceptibility, further supporting the role of these gasotransmitters in disease pathology.
The interplay between NO, CO, and H₂S represents a critical aspect of migraine pathophysiology, influencing vascular, inflammatory, and nociceptive pathways. Understanding these gasotransmitters' roles may provide novel therapeutic targets for migraine management, particularly through modulation of TRPA1-CGRP signaling and oxidative stress pathways. Further research is warranted to explore their clinical applications in migraine treatment.
一氧化氮（NO）、一氧化碳（CO）和硫化氢（H₂S）是与偏头痛病理生理学相关的生物活性气体递质。这些气体调节血管张力、伤害性感受传递和炎症途径，在偏头痛的发作和调节中起关键作用。
本综述综合了关于NO、CO和H₂S在偏头痛中作用的现有证据，重点关注它们的分子机制、相互作用和潜在的治疗意义。分析了来自人类和动物研究的数据，以阐明它们对偏头痛发病机制的贡献。
NO是一种公认的偏头痛触发因素，硝酸甘油等NO供体通过环磷酸鸟苷（cGMP）依赖性途径诱发头痛和偏头痛发作。CO在疼痛调节中与NO和cGMP信号相互作用，有助于中枢和外周伤害性感受处理。H₂S具有双重作用：虽然它与NO相互作用形成硝酰（HNO），激活瞬时受体电位锚蛋白1（TRPA1）通道并触发降钙素基因相关肽（CGRP）释放；它还通过抗氧化机制和核因子红细胞2相关因子2（Nrf2）激活表现出神经保护特性。此外，降钙素基因相关肽α（CALCA）的表观遗传修饰与偏头痛易感性有关，进一步支持了这些气体递质在疾病病理中的作用。
NO、CO和H₂S之间的相互作用是偏头痛病理生理学的一个关键方面，影响血管、炎症和伤害性感受途径。了解这些气体递质的作用可能为偏头痛治疗提供新的治疗靶点，特别是通过调节TRPA1-CGRP信号和氧化应激途径。有必要进行进一步的研究来探索它们在偏头痛治疗中的临床应用。
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