Matrix metalloproteinases (MMPs) belong to a large family of endopeptidases that regulate the pericellular environment through the cleavage of protein components of the extracellular matrix, membrane receptors and cytokines. MMP activity is controlled by the multifunctional tissue inhibitors of metalloproteinases (TIMPs). Proteases and their inhibitors are critically involved in developmental and pathological processes in numerous organs, including the brain. Global transient cerebral ischemia induces selective delayed neuronal death and neuroinflammation. We compared, in discrete vulnerable and resistant areas of the ischemic rat hippocampus, the kinetics and cellular distribution of gelatinase B and its principal inhibitor TIMP-1 and we assessed by in situ zymography, the net gelatinolytic activity at the cellular level. We show that gelatinases are expressed and active in neurons, suggesting that MMPs play a role in maintaining neural homeostasis. In the ischemic rat brain, expression and activity of gelatinase B, and expression of TIMP-1 are altered in a time-, region- and cell-dependent manner. Gelatinase B is induced first in reactive microglia and subsequently in reactive astrocytes. In situ, increases in gelatinase activity accompanied the progression of neuronal death and glial reactivity. Our results suggest that MMPs and TIMPs are involved in cell viability and tissue remodelling in the ischemic brain, and reinforces the idea that the MMP/TIMP system contributes both to neuronal demise and tissue repair in the context of glial reactivity.

Matrix Metalloproteinases (MMPs) play a role in migration of many cell types outside the central nervous system (CNS). Among neural cells, astrocytes are one of the main sources of MMPs in physiological and postlesional conditions. However, no data are available on the possible role of MMPs in astrocyte motility. Using an in vitro model of 2D migration and broad spectrum and selective MMP inhibitors, the authors demonstrated that MMP-2, but not MMP-9, is a key enzyme for astrocyte migration. In support of these data, the authors found constitutive expression of MMP-2 in astrocytes, while MMP-9 was nearly undetectable by gel zymography and immunocytochemical methods. The inhibition of migration by MMP inhibitors correlated with changes in cell morphology and in the organization of the actin cytoskeleton. In parallel, the characteristic focalized distribution of MMP-2 at the migration front observed in control cells became more diffuse and internalized by treatments that inhibited migration. The disruption of actin by cytochalasin D caused the partial recruitment of MMP-2 and gelatinolytic activity into actin aggregates, indicating a connection between the proteinase and the actin cytoskeleton. Finally, the authors found a co-localization of beta1-integrin with MMP-2 at the leading edge of migrating astrocytes. Altogether, these data provide the first evidence for the implication of MMP-2 in astrocyte motility, probably through the interaction of the proteinase with beta1-integrin that could act as a linker between pericellular proteolysis and the actin cytoskeleton.

Background: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional secreted protein with pleiotropic actions, including the inhibition of matrix metalloproteinases (MMPs), cell death/survival and growth promoting activities. After inflammatory challenge, the levels of TIMP-1 are highly and selectively upregulated in astrocytes among glial cells, but little is know about its role in these neural cells. We investigated the influence of TIMP-1 null mutation in the reactivity of cultured astrocytes to pro-inflammatory stimuli with TNF-α and anti-Fas antibody.

Les métalloprotéases matricielles (MMP) constituent une famille multigénique (près de 25 membres à ce jour) de protéases dépendantes du zinc, sécrétées ou membranaires (membrane type MMP, MT-MMP). Les MMP contrôlent par clivage protéolytique l'activité de composants de la matrice extracellulaire, des molé-cules membranaires ou solubles impliquées dans la transmission des signaux intercellulaires telles que les cytokines, les chimiokines, les facteurs trophiques, les protéines d'adhérence et différents récepteurs. Dans les tissus, l'activité protéolytique des MMP est contrô-lée par quatre inhibiteurs de MMP, les TIMP (tissue inhibitors of metalloproteinases) qui possèdent également des propriétés trophiques ou, à l'inverse, pro-apoptotiques. Le système MMP/TIMP contrôle les interactions cellule-cellule et cellule-matrice impliquées dans de nombreux processus physiologiques, notamment la prolifération, la différenciation, la migration et la mort cellulaire. Cependant, la rupture de l'équilibre protéase-inhibiteur peut entraîner dans de nombreux tissus la perte de l'homéostasie et le déve-loppement de processus dégénératifs ou cancéreux, en particulier les métastases (➜). Si le système MMP/TIMP est très étudié en dehors du système nerveux, il ne suscite l'intérêt des neurobiologistes que depuis une dizaine d'années. Nous résumons ici les données récentes qui montrent que le système MMP/TIMP joue un rôle majeur dans différents aspects de la physiologie et de la pathologie du système nerveux et que les MMP pourraient constituer de nouvelles cibles thérapeutiques dans différentes neuropathies. Le système MMP/TIMP au cours de l'ontogenèse du système nerveux et dans la plasticité neuronaleLa distribution spatio-temporelle de nombreuses MMP et des quatre TIMP varie selon le stade de développe-ment considéré. Ainsi, les variations d'expression de > Les métalloprotéases matricielles (MMP) contrôlent ou dégradent par clivage protéolytique des composants de la matrice extracellulaire, des protéines d'adhérence, des récepteurs membranaires et des protéines solubles. Le contrôle de l'activité des MMP par leurs inhibiteurs physiologiques, les TIMP (tissue inhibitors of metalloproteinases), contribue à l'homéostasie tissulaire. En revanche, la perte de ce contrôle peut être associée à des processus de prolifération ou de mort cellulaire et aux remaniements tissulaires qui caractérisent les maladies malignes et dégé-nératives de nombreux tissus n'appartenant pas au système nerveux. Cet article fait le point sur les résultats récents montrant que les MMP jouent également un rôle central dans la physiopathologie du système nerveux et qu'elles pourraient constituer de nouvelles cibles thérapeutiques dans différentes maladies du système nerveux. <

Reçu le 26 décembre 2002 RÉSUMÉ Les métalloprotéases matricielles (MMPs) régulent ou dégradent par clivage protéolytique des composants de la matrice extracellulaire, des cytokines et chimio kines, des protéines d'adhérence et de multiples récep teurs membranaires. Le contrôle de l'activité des MMPs par leurs inhibiteurs physiologiques, les TIMPs, participe à l'homéostasie tissulaire. Par contre, la perte de ce contrôle est associée à des processus patholo giques impliquant inflammation, prolifération ou mort cellulaire et remaniements tissulaires. Le système MMP/TIMP est impliqué dans le développement et la fonction des cellules du système immunitaire, en per mettant leur différenciation, leur activation, leur migration à travers les membranes basales et dans les tissus. Nous résumons ici les résultats récents qui mon trent que le système MMP/TIMP participerait non seulement aux interactions neuro-immunes mais joue rait également un rôle central dans la physiopatholo gie du système nerveux où les MMPs pourraient constituer de nouvelles cibles thérapeutiques. SUMMARY Matrix Metalloproteinases and their Inhibitors, Modulators of Neuro-Immune Interactions and of Pathophysiological Processes in the Nervous System The matrix metalloproteinases (MMPs) belong to a growing family of Zn2+-dependent endopeptidases, secreted or membrane-bound (MT-MMP), that regu late or degrade by proteolytic cleavage protein com ponents of the extracellular matrix, cytokines, che mokines, cell adhesion molecules and a variety of membrane receptors. MMP activity is counterbalan ced by their physiological inhibitors, the tissue inhi bitors of MMPs (TIMPs), a family of 4 secreted mul tifunctional proteins that have growth promoting activities. In physiological conditions MMP activity is tightly regulated and altered MMP regulation is asso ciated with pathological processes including inflam mation, cell proliferation, cell death and tissue remo deling. The MMP/TIMP system is involved in the development and function of cells of the immune sys tem by promoting their differentiation, activation, migration across basement membranes and tissues. In the last years, data has accumulated indicating that the MMP/TIMP system is expressed in the nervous system where it regulates neuro-immune interactions and plays a major role in pathophysiological pro cesses. In this review, we present recent in vivo and in vitro studies that highlight the contribution of the MMP/TIMP system to various diseases of the ner vous system, involving blood brain barrier break down, neuroinflammation, glial reactivity, neuronal death, reactive plasticity, and to developmental and physiological processes including cell migration, axo nal sprouting and neuronal plasticity. This review also alludes to the beneficial effects of synthetic MMP inhibitors in different animal models of neuropatho logy. In all, a further understanding of the role of MMPs and TIMPs in the nervous system should contribute to unravel mechanisms of neuronal plas ticity and pathology and set the basis of n...

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Summary. Storage and mobilization of tyrosine in a lepidopterous larva : assay of tyrosine, its glucoside and other amino acids in Spodoptera littoralis, a lepidopterous noctuid moth.An HPLC method has been developed for simultaneous determination of tyrosine and its 0-glucoside. Concentrations of both in whole tissues and in the haemolymph of a noctuid moth, Spodoptera littoralis, were determined through larval life. The presence of glucosides was assessed from the last larval instar on, the major site of storage being the haemolymph. In this sixth instar, the metabolism of tyrosine and its glucoside seemed to be thoroughly coupled. A rapid increase of ¡3-D-glucopyranosyl-O-L-tyrosine concentration was followed by a two-step fall at the end of the instar ; a moderate one soon after cessation of feeding and a sharp fall at pupal ecdysis due to the utilization of tyrosine for cuticle formation. Emphasis has been placed on the last larval instar and tyrosine level has been compared with the levels of other free amino-acids and peptides grouped according to their profile in the instar.Introduction.