Editorial New implications of the proteolytic balance between matrix metalloproteinases and their tissue inhibitors in migraine with and without aura Ferdinando Mannello ⁎ Department of Biomolecular Sciences, Section of Clinical Biochemistry, University “Carlo Bo” of Urbino, Via O. Ubaldini, 7 – 61029 Urbino (PU), Italy abstract article info Article history: Received 15 July 2009 Accepted 15 July 2009 Available online 24 July 2009 Keywords: Migraine with and without aura Matrix metalloproteinase-2 and -9 Tissue inhibitor of metalloproteinase-1 and -2 Headache Migraine mechanism Therapeutic application 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. © 2009 Elsevier B.V. All rights reserved. 1. From developmental biology to the pathogenesis of neurological diseases 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 [1]. Ever growing research has identified MMP expression in a variety of physiological processes, including embryonic development, morphogenesis, stem cell differ- entiation, tissue repair, and apoptosis [2–4]. Uncontrolled or inap- propriate expression/activity of MMPs contributes to different pathologic conditions, including inflammation, tumour growth, cancer cell invasion and infection diseases [2,5–7]. The MMP family consists of more than 25 members that share common domain organization (i.e., propetide and N-terminus catalytic domains); they may be classified as collagenases, gelatinases, stromelysins, membrane type, matrilysins and other MMPs [8]. The N-terminal signal domain is essential for the latency and activation mechanism of all MMPs; it contains the cysteine switch motif where an unpaired cysteine residue binds to the catalytic zinc ion: the enzyme reaches its fully active state when this bridge between the cysteine and the zinc ion is disrupted [9]. To prevent uncontrolled tissue destruction or excessive ECM remodelling, MMP activity can be inhibited by aspecific inhibitors (e.g., α2-macroglobulin) or by specific tissue inhibitors of MMPs (TIMPs), which bind MMP in a non-covalent way inactivating the enzyme [10]. The four known TIMPs share many properties but also have distinct activity, suggesting that they might have a specific physiological role, independent of their MMP-inhibitor functions [11]. Under physiological conditions, MMP activity is precisely controlled by TIMPs and may have beneficial actions in the mature nervous system (e.g., remodelling of ECM for cell migration and axonal elongation, release of growth factors, angiogenesis, process formation by oligoden- drocytes, clearance of debris following brain injury, breakdown of amyloid proteins) [12,13]. However, an alteration of the MMP/TIMP balance (e.g., due to the lack of TIMP expression and/or an excess of Clinica Chimica Acta 409 (2009) 1–3 ⁎ Tel.: +39 0722 351479; fax: +39 0722 322370. E-mail address: ferdinando.mannello@uniurb.it. 0009-8981/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2009.07.009 Contents lists available at ScienceDirect Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim