The Value and Importance of MiRNAs as Potential Biomarkers in Migraine

Migraine is among the top 10 causes of disability, yet its pathogenesis remains complex.¹ Current therapies available for migraine are shown to be effective in only a portion of patients and may also produce off-target effects. At present, researchers are studying the efficacy of precision medicine for migraine relief using data from biomarker-driven trials with the goal of improving migraine molecular profiling to result in a more effective, multidisciplinary treatment approach. In a study published in Molecular Diagnosis and Therapy, Parisa Gazerani, PharmD, PhD,  explores the role of microRNAs (miRNAs) in migraine and their potential as biomarkers to identify at-risk patients, chronification risk factors, and miRNA-based treatment options.

Researchers have recognized the value and importance of reliable biomarkers in migraine since the 1990s. Since then, potential biomarkers for migraine have been proposed,  including serotonin, glutamate, cytokines, and others; however, there are still no validated biomarkers specific to migraine because many of the proposed substances are not specific to migraine only.¹ Researchers stated that using a combination of biomarkers, as opposed to a single marker, may be of more use in understanding and effectively treating migraine.

According to the author, an ideal migraine biomarker would provide high specificity and sensitivity, allow early detection, and show significant variation in levels during different stages of migraine.¹ Researchers have identified the noncoding RNA family as a promising set of potential biomarkers because they can be divided into long or short noncoding RNAs — both classes of which have been shown to be involved in migraine. However, compared with other biomarkers in the noncoding RNA family, miRNAs have been found to offer a higher degree of stability and have been more extensively studied for their role in migraine.¹

Specific miRNAs are altered during pathological conditions, which has allowed them to be used as molecular biomarkers in the diagnosis of epilepsy, Alzheimer disease, diabetes, cardiovascular disease, and various cancers.¹ Results from a 2018 study published in Oncotarget revealed that miRNAs are involved in the pathogenesis of cardiovascular diseases and may serve as potential biomarkers.² Results from another 2018 study published in Oncology Letters confirmed that more than 50% of miRNA genes are located in genomic regions associated with cancer and form nodal points in cancer pathways, suggesting that miRNAs may play an important role in the pathogenesis of cancer.³ The identification of miRNAs in these diseases has paved the way for new research promoting their use in identifying, targeting, and treating a number of conditions, including migraine.

MiRNAs have been explored in various pain conditions and in headache for the purpose of developing potential therapeutic targets. Pain conditions in which MiRNAs become altered include visceral pain, endometriosis, fibromyalgia, osteoarthritis, rheumatoid arthritis, and complex regional pain syndrome.¹ MiRNAs regulate immune and neuronal processes that play a role in pain signaling; therefore, miRNAs may control pain modulation and serve as biomarkers for pain and analgesic response to treatment. Circulating miRNA levels are found to be altered by analgesics, which indicates miRNAs may also be effective at mediating drug effects, modifying drug response, and preventing pain.¹

The potential therapeutic impact of miRNAs in pain requires additional research because miRNA-based therapies involve crossing the blood-brain barrier and may produce off-target effects. Despite these potential roadblocks, researchers have recognized that miRNAs have high potential as biomarkers for risk assessment, drug selection, and nonpharmacological therapies for pain relief.¹

Though the exact role of miRNAs in migraine has yet to be established, researchers speculated that altered levels of miRNAs in human biofluids such as saliva can be used as potential biomarkers of cluster headache, tension headache, and migraine with and without aura. Another recent study by Dr Gazerani and colleagues investigated alterations in miRNAs that occurred during migraine attacks and pain-free periods.⁴ Of the 372 miRNAs evaluated, they identified 32 specific miRNAs that were altered in patients with migraine compared with healthy control participants. They noted that these latest findings significantly contrasted with those from another study published in 2014, which failed to demonstrate alterations of miRNAs in migraine.¹

MiRNAs have also been studied in migraine without aura to identify specific miRNAs that become altered during attacks. Researchers identified 4 differentially expressed miRNAs (miR-27b, miR-181a, let-7b, and miR-22) and concluded that a specific circulating miRNA profile is associated with migraine without aura.¹ MiRNAs have also been used to study the association between migraine and vascular dysfunction, and migraine and cardiovascular risk.

Concerning the pathogenesis of migraine, researchers are still debating the origin of pain. The author mentioned another recent study in which researchers attempted to identify extracranial sources of migraine pain by evaluating gene transcripts that encode proteins found to contribute to inflammatory and immune responses.⁵ They also assessed the number of copies of miRNAs that regulate the expression of those genes in periosteum tissue in patients with chronic migraine. Their results revealed 27 of 726 miRNAs were differentially expressed in periosteum samples in patients with chronic migraine.⁵ They also identified 25 upregulated genes that encode proinflammatory proteins, providing support for the hypothesis that expression of genes involved in inflammation may be linked to migraine.

Identifying biomarkers of migraine among youths may also be of high value because migraine can be difficult to diagnose and manage in this population. A recent study evaluated miRNA hsa-miR-34a-5p in youths with migraine because this miRNA has demonstrated increased expression in adults with migraine. The results revealed that in untreated youths with migraine without aura, hsa-miR-34a-5p was expressed at higher levels than in healthy control participants, indicating that this miRNA could be a potential biomarker for predicting therapeutic response in youths with migraine without aura.⁶

MiRNAs are continuing to be extensively researched for their use in the diagnosis and treatment of migraine and a range of other diseases and chronic pain conditions. Researchers are compiling data on the value of miRNA signatures, including the prediction of at-risk patients, patient stratification, and follow-up of patients who respond to treatment — all of which can be used in future clinical trials evaluating biomarkers. Investigations of nonpharmacological treatment of migraine and chronic pain, such as acupuncture, biofeedback, and vagal nerve stimulation, may also benefit from emerging evidence surrounding miRNAs.

Overall, researchers predicted that miRNA-based prevention and treatment for migraine and diseases will continue to be extensively evaluated and have broader applications in the near future.

References

1. Gazerani P. Current evidence on potential uses of microRNA biomarkers for migraine: from diagnosis to treatment. Mol Diagn Ther. 2019;23(6):681-694.

2. Ultimo S, Zauli G, Martelli AM, et al. Cardiovascular disease-related miRNAs expression: potential role as biomarkers and effects of training exercise. Oncotarget. 2018;9(24):17238-17254.

3. Tan W, Liu B, Qu S, Liang G, Luo W, Gong C. MicroRNAs and cancer: key paradigms in molecular therapy. Oncol Lett. 2018;15(3):2735-2742.

4. Andersen HH, Duroux M, Gazerani P. Serum MicroRNA signatures in migraineurs during attacks and in pain-free periods. Mol Neurobiol. 2016;53(3):1494-1500.

5. Burstein R, Perry C, Blake P, Buettner C, Bhasin M. EHMTI-0354. Abnormal expression of gene transcripts linked to inflammatory response in the periosteum of chronic migraine patients: implications to extracranial origin of headache [published online September 18, 2014]. J Headache Pain. 2014;15:K2.

6. Gallelli L, Cione E, Peltrone F, Siviglia S, Verano A, Chirchiglia D, et al. Hsa-miR-34a-5p and hsa-miR-375 as biomarkers for monitoring the effects of drug treatment for migraine pain in children and adolescents: a pilot study. J Clin Med. 2019;8(7):928.