Migraines are characterized by moderate to severe headache attacks and are commonly considered polygenic disorders. Typically, migraines are treated with triptans like serotonin receptor agonists; however, the mechanisms of triptans are debated upon, with these agents only effective in only about 60% of the population.
A new Scientific Reports study discusses the mechanisms of triptans for the treatment of spontaneous migraine attacks by using transcriptomics and metabolomics.
Study: Multi-omic analyses of triptan-treated migraine attacks gives insight into molecular mechanisms. Image Credit: Sjstudio6 / Shutterstock.com
Background
The global prevalence of migraines is 14.1%. Typically, migraines are characterized as severe to moderate headache attacks that can persist between four and 72 hours.
The pain of a migraine is pulsating, unilateral, and often aggravated by physical activity. Migraines may also be accompanied by vomiting, nausea, photophobia, and/or phonophobia.
Triptans, a family of tryptamine-based drugs, are an effective treatment method for migraines. However, only about 30% of patients are pain-free after two hours of taking a triptan. It is important to understand the biological mechanisms of triptans, as this may explain the lack of response in some patients.
Triptans are hydrophilic and partially cross the blood-brain barrier during a migraine attack. Furthermore, triptans are 5-HT1B/1D receptor agonists, which are G-protein coupled receptors that are similar but not identical and inhibit adenylate cyclase. By coupling to potassium (K+) and calcium (Ca2+) channels, triptans also inhibit neurotransmitter release and stimulate extracellular signal-regulated kinases (ERK) translocation.
The metabolome comprises thousands of metabolites that are final and intermediate products of metabolism. The metabolome is considered to be the closest ‘omic level to the expressed phenotype and has the potential to uncover disease and drug mechanisms by providing insights on how genes translate to function.
To date, the effect of triptans on a spontaneous migraine attack has never been studied using omics data.
About the study
In the current study, blood samples from 100 patients were collected during spontaneous migraine attacks, both before and after acute treatment with a triptan. The sample comprised 83 females and 17 males.
Untargeted metabolomics was analyzed to find alterations initiated by either the migraine attack and/or treatment. This was then integrated with transcriptomics to map molecular mechanisms.
Study findings
Three differential metabolites were detected, including cortisol, sumatriptan, and glutamine. Sumatriptan was not present during the migraine attack but only after treatment. After several hours of treatment, cortisol levels were reduced, whereas glutamine levels increased.
The collection of large sample sizes is challenging, as migraine attacks are irregular and occur outside the hospital. In this study, changes in gene- or metabolite expression were not found because of small sample size issues. Furthermore, the paired-sample design increased the statistical power, as variability was reduced by removing the potential influence of any stable individual differences, such as medication use or migraine characteristics.
Cortisol levels declined two hours after treatment. This observation was not surprising since during a migraine attack, the stress hormone is expected to rise and then reduce following treatment. However, this metabolite was not found to be up-regulated after the cold-pressor test.
Sumatriptan was detected in the blood following treatment. The integration of transcriptomics with the change in sumatriptan showed a correlation with G protein subunit alpha I1 (GNAI1), which eventually led to decreased levels of cyclic adenosine monophosphate (cAMP). A correlation with vasoactive intestinal peptide receptor 2 (VIPR2) was also observed.
Several substances that cause upregulation of cAMP, including CGRP22 and PACAP23, can cause migraine attacks. A potential mechanism for successful treatment is the downregulation of cAMP25.
Among the metabolites, a positive correlation was observed between sumatriptan and palmitoylcarnitine. Palmitoylcarnitine plays an important role in the transport of long-chain fatty acids into the mitochondria for energy production. This is consistent with prior research showing changes in gene expression during the triptan-treated migraine attack.
Increased levels of glutamine were also observed after treatment. Prior research has shown the importance of the glutamatergic system in migraines.
Sumatriptan reduces neurotransmitter release by inhibiting glutamatergic synaptic transmission. The increased levels of glutamine could arise in an effort to balance the glutamatergic system.
This hypothesis is strengthened by the observation that the higher level of glutamine was positively correlated with γ-Glu Gln, which is a dipeptide of glutamine joined to the gamma-carbon of glutamate.
Glutamine is also an energy source for immune cells; therefore, high glutamine levels could reflect increased activity of the immune system. Among correlated metabolites, several carnitines, including O-acetylcarnitine, acetylcarnitine, and hydroxybutyrylcarnitine were found, which supports the importance of fatty acid oxidation in migraines and their treatment.
Conclusions
This study's findings demonstrate the effect of regulating cAMP levels, a key mechanism of triptans. The upregulation of glutamine after migraine treatment could be driven by the migraine attack or treatment with triptan.
These findings also emphasize the importance of cAMP and fatty acid oxidation in the molecular mechanisms of sumatriptan.
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