FINAL REPORT: Developing a pragmatic human model suitable for migraine drug testing combined with the study of biochemical changes during a migraine attack in humans

Summary

There is a great need for more effective anti-migraine drugs. In order for this to happen, it is necessary to develop a valid human model for the testing of drug candidates. We developed such a model and MRF awarded us a grant to validate it. While validating this model, we also planned to use advanced proteomic techniques to observe biochemical changes in human plasma, potentially leading to the identification of specific biomarkers for migraine.

Rather than wait for spontaneous migraine attacks to occur, we induced a headache in migraine without aura (MO) patients using the drug cilostazol. We then attempted to abort the headache with sumatriptan, the most common triptan medication. While we were successful in inducing a migraine-like headache in all cases, sumatriptan was not effective in relieving the cilostazol-induced headache compared to control patients who received a placebo.

In order to find biomarkers for migraine, we collected blood samples from MO patients during migraine, outside migraine and after sumatriptan intervention. We analyzed the blood plasma for a number of neuropeptides and other migraine relevant small molecules including CGRP (calcitonin gene-related peptide), histamine, L-Kynurenine and Kynurenic acid. In most of the samples, CGRP concentration and histamine levels were below the lower limit of quantification. There was no significant change in Kynurenic acid or Kynurenine levels.

Hypotheses vs. Findings

In the first study, we hypothesized that we could induce migraine-like headaches using cilostazol and then abort the headaches with sumatriptan to validate our drug-testing model. Although cilostazol administration induced migraine-like headache in all MO patients, sumatriptan intervention was not effective in reducing headaches compared to the placebo group.

In the second study, we aimed to learn about the pathogenesis of migraine by studying neuropeptides and other migraine relevant small molecules in the plasma collected from MO patients. There was no significant change in plasma CGRP, histamine, Kynurenic acid or L-Kynurenine levels during or outside migraine and no change after sumatriptan intervention. As a result, we were not successful in identifying specific biomarkers for migraine in blood plasma.

Unanswered Questions

We found that drug-induced migraine-like attacks were non-responsive to sumatriptan, whereas spontaneous migraine attacks are often helped by sumatriptan. This signifies that migraine is a complex neurovascular disorder and experimental migraine models are not identical to spontaneous migraine attacks. We need to develop a better way to mimic spontaneous attacks in order to have a robust platform for testing new migraine drug candidates.

What this Research Means to You

The need remains to develop an effective methodology for mimicking spontaneous migraine headaches in order to test drug candidates for relieving headaches. A successful testing platform would attract drug industry interest in developing migraine-specific medications. Migraine remains a complex disorder and further research is necessary to identify specific biomarkers that would allow doctors to diagnose migraine more easily and effectively.