Fila Michal, Pawlowska Elzbieta, Krekora Jan, Mitus-Kenig Maria, Blasiak Janusz
Department of Developmental Neurology and Epileptology, Polish Mother's Memorial Hospital Research Institute, Lodz, 93-338, Poland.
Department of Pediatric Dentistry, Medical University of Lodz, Lodz, 92-217, Poland.
J Headache Pain. 2025 Sep 1;26(1):191. doi: 10.1186/s10194-025-02114-z.
BACKGROUND: Epigenetic studies in migraine provided results on the occurrence or lack of epigenetic modifications of genes whose products are important in migraine pathogenesis. However, these studies focus on single genes without analyzing how epigenetic modifications can affect complex signaling pathways. This narrative/hypothesis review aims to provide information on how the reactive oxygen and nitrogen species (RONS)-transient receptor potential cation channel subfamily A member 1 (TRPA1)-calcitonin gene-related peptide (CGRP) axis functions, suggesting that its epigenetic modifications could be a significant factor in migraine pathophysiology. MAIN BODY: Oxidative stress is both a cause and a consequence of migraine, and reactive oxygen and nitrogen species (RONS), like other noxious stimuli, may activate the transient receptor potential cation channel subfamily A member 1 (TRPA1) to send pain signals. Methylation of the TRPA1 gene correlates with various pain states; however, the results of these studies are largely inconsistent. DNA methylation and the action of non-coding RNAs are important in the alternative RNA processing of the calcitonin-related polypeptide alpha (CALCA) gene and its transcript to produce calcitonin gene-related peptide (CGRP). The release of CGRP and substance P from trigeminal neuron terminals, mediated by TRPA1 activation and involving mitogen-activated protein kinase 1/2, is a primary mechanism driving migraine headaches. Epigenetic memory may be related to neural plasticity and migraine chronification. Therefore, the RONS-TRPA1-CGRP signaling pathways may be important in migraine pathogenesis, as demonstrated in experimental animals by the phenomenon of cortical spreading depolarization. CONCLUSION: The RONS-TRPA1-CGRP axis plays a significant role in the pathogenesis of migraine and other pain-related syndromes. Epigenetic modifications of the genes encoding the components of the antioxidant defense system, TRPA1 and CGRP, are crucial in migraine pathogenesis, prevention, and therapy. However, due to the sequence specificity of the axis, only non-coding RNAs can currently be considered for therapeutic intervention in migraine, targeting the epigenetic profile of the RONS-TRPA1-CGRP axis.
背景：偏头痛的表观遗传学研究揭示了在偏头痛发病机制中发挥重要作用的基因发生或未发生表观遗传修饰的相关结果。然而，这些研究聚焦于单个基因，并未分析表观遗传修饰如何影响复杂的信号通路。本叙述性/假说性综述旨在提供有关活性氧和氮物种（RONS）-瞬时受体电位阳离子通道亚家族A成员1（TRPA1）-降钙素基因相关肽（CGRP）轴功能的信息，表明其表观遗传修饰可能是偏头痛病理生理学中的一个重要因素。 主体内容：氧化应激既是偏头痛的一个病因，也是其结果，活性氧和氮物种（RONS）与其他有害刺激一样，可能激活瞬时受体电位阳离子通道亚家族A成员1（TRPA1）以发送疼痛信号。TRPA1基因的甲基化与多种疼痛状态相关；然而，这些研究的结果在很大程度上并不一致。DNA甲基化和非编码RNA的作用在降钙素相关多肽α（CALCA）基因及其转录本的可变RNA加工以产生降钙素基因相关肽（CGRP）过程中很重要。由TRPA1激活介导并涉及丝裂原活化蛋白激酶1/2，三叉神经元终末释放CGRP和P物质是引发偏头痛的主要机制。表观遗传记忆可能与神经可塑性和偏头痛慢性化有关。因此，如实验动物中皮质扩散性去极化现象所表明的，RONS-TRPA1-CGRP信号通路可能在偏头痛发病机制中起重要作用。 结论：RONS-TRPA1-CGRP轴在偏头痛及其他疼痛相关综合征的发病机制中起重要作用。编码抗氧化防御系统成分、TRPA1和CGRP的基因的表观遗传修饰在偏头痛发病机制、预防和治疗中至关重要。然而，由于该轴的序列特异性，目前偏头痛的治疗干预仅可考虑针对RONS-TRPA1-CGRP轴的表观遗传特征的非编码RNA。
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