Substance P (SP), calcitonin gene-related peptide (CGRP), and angiotensin converting enzyme (ACE) may have roles in trigeminovascular nociceptive mechanisms. We investigated interictal levels of SP, CGRP, ACE activity, and their correlation, in a sample of migraineurs. Forty-one patients suffering from migraine with aura (MA), 54 without aura (MO), and 52 non-headache subjects (controls) participated in this study. Blood samples were collected from cubital veins. Plasma levels of SP and CGRP were measured by enzyme immunoassay. Plasma ACE activities were measured spectrophotometrically. SP levels in MA (6.6+/-3.7 pg/ml; mean+/-SD) and MO (6.6+/-3.2 pg/ml) were significantly higher than in controls (4.8+/-2.4 pg/ml) (P<0.01). CGRP levels in MA (18.8+/-8.8 pg/ml) and MO (19.1+/-9.4 pg/ml) were also significantly higher than in controls (13.4+/-4.4 pg/ml) (P<0.01). ACE activities in MA (34.6+/-19.0 U/l) were significantly higher than in MO (25.3+/-13.2 U/l) and controls (27.0+/-20.4 U/l) (P<0.05). There was a significant correlation between SP and CGRP levels (P<0.05). In MA, SP and CGRP showed a tendency toward positive correlation, which was not significant. There was a weak, but significant positive correlation between SP levels and ACE activities (P<0.01). However, a relationship between ACE activities and CGRP levels was not observed. The data suggest that SP, CGRP, and ACE are relevant to migraine pathophysiology, and that they may interact.

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Background and Objective.-Cortical spreading depression and neurogenic inflammation have been hypothesized to be key steps in the development of migraine headache. Recent studies have highlighted matrix metalloproteinase-9 (MMP-9) in cortical spreading depression, neurogenic inflammation, and cerebral ischemia. To seek their possible association, we investigated plasma MMP-9 levels in migraineurs during headache-free periods.Methods.-Plasma MMP-9 levels in 84 migraine subjects and 61 controls were determined by enzyme-linked immunosorbent assay. In addition, 23 patients with tension type headache were included in the study as comparative subjects.Results.-The MMP-9 levels in migraineurs (42.5 Ϯ 4.6 ng/mL, mean Ϯ SE) were significantly higher than those in controls (25.4 Ϯ 2.7 ng/mL, P < .005). Those levels in tension type headache subjects (24.6 Ϯ 4.8 ng/mL) did not differ from those in controls. There was no significant difference between subjects having migraine with aura and those without aura. The MMP-9 levels did not correlate with age, duration of illness, frequency of migraine attack, duration of headache attack, or medication for headache. Mean plasma MMP-9 levels were the highest in subjects from whom blood samples were taken 2-4 days after their latest attack.Conclusions.-The degradation of extracellular matrix showing the increase of MMP-9 in migrainurs may be associated with an abnormality in their blood vessel permeability. MPP-9 plays some role in migraine pathophysiology. Further studies of MMPs are necessary to elucidate their role.Key words: cortical spreading depression, gelatinase, ischemia, neurogenic inflammation, migraine Abbreviations: BBB blood-brain barrier, CSD cortical spreading depression, ECM extracellular matrix, IL-1b interleukin-1b, MMP matrix metalloproteinase, MMP-9 matrix metalloproteinase-9, TNF-a tumor necrosis factor-a (Headache 2007;48:135-139)

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