Evidence for Altered Epigenetic Regulatory Machinery in Migraine: A Peripheral Blood Study

Calcitonin gene-related peptide (CGRP), encoded by the CALCA gene, plays a central role in migraine pathophysiology; however, it remains unclear whether migraine is associated with persistent systemic molecular alterations affecting the CGRP pathway during the interictal phase. Transient receptor potential cation channel subfamily A member 1 (TRPA1) stimulates the release of CGRP from nerve endings. We investigated gene-specific and global epigenetic regulatory mechanisms associated with CALCA and TRPA1 expression in the peripheral blood of 56 patients with episodic migraine in the interictal phase and 36 headache-free controls. Expression of CALCA, TRPA1, and genes encoding epigenetic regulators, histone deacetylases 1 and 6 (HDAC1 and HDAC6), was assessed by quantitative real-time PCR. DNA methylation of CALCA and TRPA1 was evaluated using methylation-specific PCR. Expression of other epigenetic regulators miRNA-375, miRNA-382, and miRNA-34a was determined using TaqMan MicroRNA assays. No significant differences were observed between migraine patients and controls in CALCA or TRPA1 expression, nor in DNA methylation of these genes. Similarly, no differences were found in the expression of miRNA-375 and miRNA-382. In contrast, miRNA-34a expression was significantly reduced in migraine patients. Moreover, the expression of HDAC1 and HDAC6 was significantly decreased in migraine. Despite the established role of CGRP in migraine, no evidence of persistent systemic dysregulation of CALCA or TRPA1 was detected in peripheral blood during the interictal phase. However, altered expression of miRNA-34a, HDAC1, and HDAC6 suggests the presence of broader epigenetic and post-transcriptional regulatory disturbances. These findings support a model in which migraine is associated with dysregulation of regulatory mechanisms rather than stable alterations of individual target genes.