Genome-wide DNA methylation analysis in an antimigraine-treated preclinical model of cortical spreading depolarization

Marta Vila-Pueyo, Ester Cuenca-León, Ana C. Queirós, Marta Kulis, Cèlia Sintas, Bru Cormand, José Ignacio Martín-Subero, Patricia Pozo-Rosich*, Noèlia Fernàndez-Castillo, Alfons Macaya

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review


Background: Cortical spreading depolarization, the cause of migraine aura, is a short-lasting depolarization wave that moves across the brain cortex, transiently suppressing neuronal activity. Prophylactic treatments for migraine, such as topiramate or valproate, reduce the number of cortical spreading depression events in rodents. Objective: To investigate whether cortical spreading depolarization with and without chronic treatment with topiramate or valproate affect the DNA methylation of the cortex. Methods: Sprague-Dawley rats were intraperitoneally injected with saline, topiramate or valproate for four weeks when cortical spreading depolarization were induced and genome-wide DNA methylation was performed in the cortex of six rats per group. Results: The DNA methylation profile of the cortex was significantly modified after cortical spreading depolarization, with and without topiramate or valproate. Interestingly, topiramate reduced by almost 50% the number of differentially methylated regions, whereas valproate increased them by 17%, when comparing to the non-treated group after cortical spreading depolarization induction. The majority of the differentially methylated regions lay within intragenic regions, and the analyses of functional group over-representation retrieved several enriched functions, including functions related to protein processing in the cortical spreading depolarization without treatment group; functions related to metabolic processes in the cortical spreading depolarization with topiramate group; and functions related to synapse and ErbB, MAPK or retrograde endocannabinoid signaling in the cortical spreading depolarization with valproate group. Conclusions: Our results may provide insights into the underlying physiological mechanisms of migraine with aura and emphasize the role of epigenetics in migraine susceptibility.

Original languageEnglish
Pages (from-to)3331024221146317
Number of pages12
Issue number2
Publication statusPublished - Feb 2023


  • animal models
  • Cortical spreading depolarization (CSD)
  • DNA methylation
  • epigenetics
  • migraine
  • migraine aura
  • prophylactic treatment
  • topiramate
  • valproate
  • Rats
  • Cortical Spreading Depression/physiology
  • Rats, Sprague-Dawley
  • DNA Methylation
  • Animals
  • Topiramate/pharmacology
  • Valproic Acid/pharmacology
  • Migraine Disorders/drug therapy


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