Table 3.

Direct and indirect evidence that migraine pathophysiology is also correlated to a BBB dysfunction.

Barrier	Model	Main outcomes	Reference
BBB	Cortical spread depression (CSD) model, in sprague–dawley rats and mice.	Direct evidence: brain edema and plasma protein leakage, associated with altered expression ZO-1, EBA, and immunoreactive laminin. Albumin leakage was suppressed by the injection of the matrix metalloproteinase inhibitor GM6001 and was not found in MMP9-null mice. Such results indicate that the BBB disruption related to CSD depends on the MMP-9 activity.	Gursoy-Ozdemir et al. (2004)
BBB	Familial hemiplegic migraine patients.	Direct evidence: quantitative analysis of gadolinium-enhanced MRI showed a mild, but significant, left-hemispheric opening of the BBB, preceding cortical edema.	Dreier et al. (2005)
BBB	Migraine patients	Indirect evidence: no differences in MMP-9 and TIMP-1 levels were found between ictal and interictal periods. However, lower plasma levels of MMP-3 were observed in the external jugular and cubital vein during migraine attacks. Such results suggest that plasma levels of MMP-9 might not be the most recommended biomarker of BBB disruption in migraine without aura. On the other hand, MMP-3 levels should be further investigated.	Ashina et al. (2010)
BBB	Migraine patients	Indirect evidence: higher MMP activity was associated with migraine, independent of aura symptoms.	Bernecker et al. (2011)
BBB	Migraine patients	Indirect evidence: patients presenting migraine without aura showed increased plasma concentrations of MMP-9 concentrations than migraine with aura patients.	Martins-Oliveira et al. (2012)
BBB	Migraine patients	Indirect evidence: patients with migraine with aura exhibited grater plasma concentrations of MMP-2 and MMP-2/TIMP-2 ratios than patients with migraine without aura and controls. CC genotype for C-735T polymorphism and the CC haplotype were linked to higher plasma MMP-2 concentrations in the migraine with aura group.	Gonçalves et al. (2013)