Migraine susceptibility is modulated by food triggers and analgesic overuse via sulfotransferase inhibition

Doga Vuralli; Burak Arslan; Elif Topa; Andreia Lopes de Morais; Ozlem Gulbahar; Cenk Ayata; Hayrunnisa Bolay

doi:10.1186/s10194-022-01405-z

Migraine susceptibility is modulated by food triggers and analgesic overuse via sulfotransferase inhibition

J Headache Pain. 2022 Mar 14;23(1):36. doi: 10.1186/s10194-022-01405-z.

Authors

Doga Vuralli^{1

2}, Burak Arslan³, Elif Topa⁴, Andreia Lopes de Morais², Ozlem Gulbahar³, Cenk Ayata^#^{2

5}, Hayrunnisa Bolay^#⁶

Affiliations

¹ Department of Neurology and Algology, Neuropsychiatry Center, Neuroscience and Neurotechnology Center (NÖROM), Gazi University Faculty of Medicine, Besevler, Ankara, Turkey.
² Neurovascular Research Lab, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, MA, Charlestown, USA.
³ Department of Medical Biochemistry, Gazi University Faculty of Medicine, Besevler, Ankara, Turkey.
⁴ Neuropsychiatry Center, Gazi University, Besevler, Ankara, Turkey.
⁵ Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MA, Charlestown, USA.
⁶ Department of Neurology and Algology, Neuropsychiatry Center, Neuroscience and Neurotechnology Center (NÖROM), Gazi University Faculty of Medicine, Besevler, Ankara, Turkey. hbolay@gazi.edu.tr.

^# Contributed equally.

Abstract

Background/aim: Certain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and play role in the metabolism of neurotransmitters. We aimed to dissect SULT1A1 modulation of CSD susceptibility and behavior in an in vivo experimental model using hesperidin, a SULT1A1 inhibitor found in citrus fruits (known migraine triggers) and mefenamic acid (SULT1A1 inhibitor), an NSAID to simulate medication overuse.

Methods: Hesperidin was used as SULT1A1 inhibitor found in citrus fruits, known migraine triggers and mefenamic acid (NSAID), another SULT1A1 inhibitor, was used to induce MO in rats. The groups were; 1) Hesperidin (ip) or its vehicle-DMSO (ip) 2) Chronic (4 weeks) mefenamic acid (ip) or its vehicle (ip) 3) Chronic mefenamic acid+hesperidin (ip) or DMSO (ip). CSD susceptibility was evaluated and behavioral testing was performed. SULT1A1 enzyme activity was measured in brain samples.

Results: Single-dose of hesperidin neither changed CSD susceptibility nor resulted in any behavioral change. Chronic mefenamic acid exposure resulted in increased CSD susceptibility, mechanical-thermal hypersensitivity, increased head shake, grooming and freezing and decreased locomotion. Single dose hesperidin administration after chronic mefenamic acid exposure resulted in increased CSD susceptibility and mechanical-thermal hypersensitivity, increased freezing and decreased locomotion. SULT1A1 enzyme activity was lower in mefenamic acid and mefenamic acid+hesperidin groups compared to their vehicles.

Conclusion: Mefenamic acid and hesperidin have synergistic effect in modulating CSD susceptibility and pain behavior. Sulfotransferase inhibition may be the common mechanism by which food triggers and NSAIDs modulate migraine susceptibility. Further investigations regarding human provocation studies using hesperidin in migraine patients with medication overuse are needed.

Keywords: Cortical spreading depression; Medication overuse; Migraine food triggers; SULT1A1.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Humans
Mefenamic Acid* / metabolism
Mefenamic Acid* / pharmacology
Mefenamic Acid* / therapeutic use
Migraine Disorders* / chemically induced
Migraine Disorders* / drug therapy
Prescription Drug Overuse
Rats
Sulfotransferases / therapeutic use

Substances

Anti-Inflammatory Agents, Non-Steroidal
Mefenamic Acid
Sulfotransferases

Grants and funding

2016 IHS fellowship award/International Headache Society