New implications of the proteolytic balance between matrix metalloproteinases and their tissue inhibitors in migraine with and without aura.

Matrix metalloproteinases (MMP) are proteolytic enzymes involved in the remodelling of almost all protein components of the extracellular matrix (ECM), characterized in 1960's during the metamorphosis process in tadpole tails. Ever growing research has identified MMP expression in a variety of physiological processes. Uncontrolled or inappropriate expression/activity of MMPs contributes to different pathologic conditions, including inflammation, tumour growth, cancer cell invasion and infection diseases. Under physiological conditions, MMP activity is precisely controlled by TIMPs and may have beneficial actions in the mature nervous system. However, an alteration of the MMP/TIMP balance is thought to be a key feature of the pathology of many inflammatory, degenerative and malignant neurological diseases; their pathogenesis is correlated to the detrimental effects of altered MMP/TIMP expression, leading to breakdown of the blood-brain barrier (BBB), demyelination, cytokine production and propagation of inflammatory response, deposition of amyloid proteins, tumor invasion and metastasis). Migraine is a complex, disabling disorder of the brain that manifests itself as attacks of often severe, throbbing head pain with sensory sensitivity to light, sound, smell and head movement (migraine without aura), and in a third of patients, with neurological symptoms (migraine with aura). In this issue of Clinica Chimica Acta, Martins-Oliveira et al. examine the different circulating MMP and TIMP profiles in women with migraine with and without aura. They confirm and expand the observation of increased MMP-9 plasma levels in migrainous patients, also describing for the first time that MMP-2, TIMP-1 and TIMP-2 show a different expression profile in migraine. Their findings are critically evaluated and reviewed. The knowledge of MMP- and TIMP-dependent pathways in migraine headache, the new proteolytic pathophysiological mechanisms, and the beneficial and detrimental effects of MMP inhibitory drugs may represent pieces of the complex migraine jigsaw puzzle, which is finalized to optimize cost-effectiveness of treatment and patient outcomes.