PROSTAGLANDIN-E2 LEVELS OVER THE COURSE OF GLYCERYL TRINITRATE PROVOKED MIGRAINE ATTACKS 107 5 that various mediators must be involved in slower cascades of events leading to a migraine-like attack. Evidence for cross talk is that both the administration of CGRP (pathway via cAMP) and sildenafil (pathway via cGMP) can lead to a migraine-like attack, suggesting that convergence to a common cellular determinator seem to exist ultimately triggering similar attacks.48 Given that the median time until an attack for CGRP is ~165 minutes, so much shorter than the ~285 minutes for sildenafil, one can envisage that CGRP acts more downstream in the generation of a migraine attack. Such sequential actions, given the cross talk between CGRP and PGE2, especially in GTN-induced attacks, seems in line with a chain-of-events-pathway (Figure 2). Our study has several limitations. We collected a large number of blood samples of migraine participants and healthy controls. Each participant was sampled at three fixed times during the study day in an attempt to measure PGE2 concentrations during attack development and during the attack itself. We find that the 95% confidence interval of the change in PGE2 levels from interictal to another phase extends from -0.02 to 0.05 ng/mL. Of course, the onset of the attack varies between subjects and did not align perfectly with the measurement times. Moreover, we must account for a possible temporal effect of the GTN infusion on PGE2 concentrations. Combined with within and between subject measurement variation, we must acknowledge that not finding a statistically significant difference in PGE2 levels over the course of an induced migraine-like attack does not prove the absence of such an effect. There may yet exist subtle, short-duration, variations in PGE2 levels that we could not detect. Furthermore, we have used LC-MS/MS which is distinct from the more often used ELISA kits to measure PGE2, this might make it difficult to compare absolute concentrates between studies. However, by using this method we were able to detect very low levels of PGE2 with good accuracy, despite the short half-life of PGE2. Furthermore, whereas we did not observe changes in PGE2 levels in blood it is conceivable that levels may be different in cerebrospinal fluid, as increased PGE2 levels have been reported indicative for probable Alzheimer’s disease.49 However, we deem it too unethical and unlikely that subjects with migraine (and controls) are willing to participate in a provocation study with, logically, repeated lumbar punctures to get information on PGE2 levels over time. Finally, our study only consists of females to prevent any sex effects, which may limit the generalizability of our findings to male migraine patients. Additionally, although we have performed our study in a female only population to account for the most notable sex hormone differences, small differences in cycle and use of contraceptives might be of influence in the downstream provocation pathways.
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