Matrix metalloproteinase‐9 (MMP‐9) is a member of the metzincin family of mostly extracellularly operating proteases. Despite the fact that all of these enzymes might be target promiscuous, with ...largely overlapping catalogs of potential substrates, MMP‐9 has recently emerged as a major and apparently unique player in brain physiology and pathology. The specificity of MMP‐9 may arise from its very local and time‐restricted actions, even when released in the brain from cells of various types, including neurons, glia, and leukocytes. In fact, the quantity of MMP‐9 is very low in the naive brain, but it is markedly activated at the levels of enzymatic activity, protein abundance, and gene expression following various physiological stimuli and pathological insults. Neuronal MMP‐9 participates in synaptic plasticity by controlling the shape of dendritic spines and function of excitatory synapses, thus playing a pivotal role in learning, memory, and cortical plasticity. When improperly unleashed, MMP‐9 contributes to a large variety of brain disorders, including epilepsy, schizophrenia, autism spectrum disorder, brain injury, stroke, neurodegeneration, pain, brain tumors, etc. The foremost mechanism of action of MMP‐9 in brain disorders appears to be its involvement in immune/inflammation responses that are related to the enzyme's ability to process and activate various cytokines and chemokines, as well as its contribution to blood–brain barrier disruption, facilitating the extravasation of leukocytes into brain parenchyma. However, another emerging possibility (i.e., the control of MMP‐9 over synaptic plasticity) should not be neglected. The translational potential of MMP‐9 has already been recognized in both the diagnosis and treatment domains. The most striking translational aspect may be the discovery of MMP‐9 up‐regulation in a mouse model of Fragile X syndrome, quickly followed by human studies and promising clinical trials that have sought to inhibit MMP‐9. With regard to diagnosis, suggestions have been made to use MMP‐9 alone or combined with tissue inhibitor of matrix metalloproteinase‐1 or brain‐derived neurotrophic factor as disease biomarkers.
MMP‐9, through cleavage of specific target proteins, plays a major role in synaptic plasticity and neuroinflammation, and by those virtues contributes to brain physiology and a host of neurological and psychiatric disorders.
This article is part of the 60th Anniversary special issue.
MMP‐9, through cleavage of specific target proteins, plays a major role in synaptic plasticity and neuroinflammation, and by those virtues contributes to brain physiology and a host of neurological and psychiatric disorders.
This article is part of the 60th Anniversary special issue.
Ischemic stroke is a leading cause of disability worldwide. In cerebral ischemia there is an enhanced expression of matrix metallo-proteinase-9 (MMP-9), which has been associated with various ...complications including excitotoxicity, neuronal damage, apoptosis, blood–brain barrier (BBB) opening leading to cerebral edema, and hemorrhagic transformation. Moreover, the tissue plasminogen activator (tPA), which is the only US-FDA approved treatment of ischemic stroke, has a brief 3 to 4 h time window and it has been proposed that detrimental effects of tPA beyond the 3 h since the onset of stroke are derived from its ability to activate MMP-9 that in turn contributes to the breakdown of BBB. Therefore, the available literature suggests that MMP-9 inhibition can be of therapeutic importance in ischemic stroke. Hence, combination therapies of MMP-9 inhibitor along with tPA can be beneficial in ischemic stroke. In this review we will discuss the current status of various strategies which have shown neuroprotection and extension of thrombolytic window by directly or indirectly inhibiting MMP-9 activity. In the introductory part of the review, we briefly provide an overview on ischemic stroke, commonly used models of ischemic stroke and a role of MMP-9 in ischemia. In next part, the literature is organized as various approaches which have proven neuroprotective effects through direct or indirect decrease in MMP-9 activity, namely, using biotherapeutics, involving MMP-9 gene inhibition using viral vectors; using endogenous inhibitor of MMP-9, repurposing of old drugs such as minocycline, new chemical entities like DP-b99, and finally other approaches like therapeutic hypothermia.
Matrix metalloproteinases (MMPs) are a group of over twenty proteases, operating chiefly extracellularly to cleave components of the extracellular matrix, cell adhesion molecules as well as cytokines ...and growth factors. By virtue of their expression and activity patterns in animal models and clinical investigations, as well as functional studies with gene knockouts and enzyme inhibitors, MMPs have been demonstrated to play a paramount role in many physiological and pathological processes in the brain. In particular, they have been shown to influence learning and memory processes, as well as major neuropsychiatric disorders such as schizophrenia, various kinds of addiction, epilepsy, fragile X syndrome, and depression. A possible link connecting all those conditions is either physiological or aberrant synaptic plasticity where some MMPs, e.g., MMP-9, have been demonstrated to contribute to the structural and functional reorganization of excitatory synapses that are located on dendritic spines. Another common theme linking the aforementioned pathological conditions is neuroinflammation and MMPs have also been shown to be important mediators of immune responses.
Matrix metalloproteinases (MMPs) are either secreted or membrane-bound proteases, capable to degrade extracellular matrix (ECM) proteins as well as a large number of non-ECM proteins, such as growth ...factors, cytokines, chemokines, cell surface receptors, serine proteinase inhibitors and other MMPs. MMPs play major physiological roles in reproduction, growth, development, angiogenesis, immune response, wound healing and brain physiology. MMPs, and especially MMP-2 and -9 were considered to be targets for drug development (especially in oncology) and over fifty MMP inhibitors have been pursued in clinical trials that, however, failed mainly for the reason of insufficient knowledge about complexity of the biology. Recent studies implicating MMP-9 in aberrant synaptic plasticity underlying neuropsychiatric disorders, as well as in aggravating detrimental effects of the brain stroke, appear to offer a new hope for application of MMP inhibitors in treatment of those conditions.
Since the 1980s, we have witnessed the rapid development of genetically modified mouse models of human diseases. A large number of transgenic and knockout mice have been utilized in basic and applied ...research, including models of neurodegenerative and neuropsychiatric disorders. To assess the biological function of mutated genes, modern techniques are critical to detect changes in behavioral phenotypes. We review the IntelliCage, a high-throughput system that is used for behavioral screening and detailed analyses of complex behaviors in mice. The IntelliCage was introduced almost two decades ago and has been used in over 150 studies to assess both spontaneous and cognitive behaviors. We present a critical analysis of experimental data that have been generated using this device.
This paper presents the results of experimental studies on the transport of water-sandy mixtures with the content of very fine non-cohesive fractions in steady flow. The flow and shear velocity ...measurements as well as the measurements of sediment amount in the trap and control area were conducted. A theoretical model of the vertical structure of both velocity and concentration of sediment non-cohesive fractions as well as vertical mixing and sorting is presented here for transport calculations. The interaction effects between fractions are included, especially the influence of fine fractions in the mixture on transport of coarser fractions. The model provides an agreement between measurements and calculations of transport rate and grain size distributions of poorly sorted mixtures within plus/minus a coefficient of two. Further, the present model is used for calculating the limited contribution of very fine fractions in sediment due to deficit of those fractions in the bed. Again, the compliance of the calculations of sediment transport according to measurements is achieved. The satisfactory agreement between the calculations of grain size distributions and measurements is also found.
Zif268 is a transcription regulatory protein, the product of an immediate early gene. Zif268 was originally described as inducible in cell cultures; however, it was later shown to be activated by a ...variety of stimuli, including ongoing synaptic activity in the adult brain. Recently, mice with experimentally mutated zif268 gene have been obtained and employed in neurobiological research. In this review we present a critical overview of Zif268 expression patterns in the naive brain and following neuronal stimulation as well as functional data with Zif268 mutants. In conclusion, we suggest that Zif268 expression and function should be considered in a context of neuronal activity that is tightly linked to neuronal plasticity.
The feature of self-cleansing in sewer pipes is a standard requirement in the design of drainage systems, as sediments deposited on the channel bottom cause changes in channel geometric properties ...and in hydrodynamic parameters, including the friction caused by the cohesive forces of sediment fractions. Here, it is shown that the content of cohesive fractions significantly inhibits the transport of non-cohesive sediments. This paper presents an advanced calculation procedure for estimating flushing flows in channels. This procedure is based on innovative predictive models developed for non-cohesive and granulometrically heterogeneous sediment transport with additional cohesive fraction content to estimate the magnitude of increased flow necessary to ensure self-cleansing of channels. The computations according to the proposed procedure were carried out for a wide range of hydrodynamic conditions, two grain diameters, six cohesive (clay) fraction additive contents and two critical stress values. The trend lines of calculations were composed with the results of experimental studies in hydraulic flumes.
ABSTRACT
Human studies indicate that high impulsivity, novelty seeking and anxiety predispose individuals to alcohol abuse. Unclear, however, is whether the same phenotypes can be observed in ...laboratory animals prone to uncontrolled alcohol drinking. To characterize a novelty‐seeking trait, anxiety, impulsivity, compulsivity and the motivation for natural rewards in mice, numerous tests were performed in the automated IntelliCage learning system. The same mice then had extended access to alcohol for 70 days, followed by the evaluation of addiction‐like behaviors, including (1) the motivation for alcohol in a progressive‐ratio schedule of reinforcement; (2) persistent and compulsive alcohol seeking and taking during signaled ‘no alcohol’ periods and (3) when subjected to punishment; and (4) the intensity of relapse after alcohol withdrawal. Our data suggest that high levels of anxiety‐related traits (i.e. low novelty seeking, low resistance to punishment and a high level of compulsive behaviors) and high impulsivity predict addiction‐like alcohol drinking in mice. Future studies are, however, warranted to create a valid model of alcohol addiction in mice in the IntelliCage system.
This paper introduces a three-layer system, proposing a comprehensive model of granular mixture transport over a mobile sloped bed in a steady flow. This system, consisting of the bottom, contact, ...and upper zones, provides complete, continuous sediment velocity and concentration vertical profiles. The aim of this study is to develop and experimentally verify this model for sediment transport over a bottom locally sloping in line with or opposite the direction of sediment flow. The model considers gravity’s effect on sediment transport in the bottom (dense) layer when the component of gravity parallel to the bottom acts together with shear stresses associated with water flow. This is a crucial factor often overlooked in previous studies. This effect causes an increase in velocity in the mobile sublayer of the dense layer and significantly affects the vertical distributions of velocity and concentration above this layer. The proposed shear variation due to the interaction between fractions and an intensive sediment mixing and sorting process over a mobile sloped bed adds to the novelty of our approach. The data sets used for the model’s validation cover various conditions, including slopes, grain diameters, densities, and grain mobility conditions, from incipient motion to a fully mobilized bed. This extensive validation process instils confidence in the theoretical description and its applicability to real-world scenarios in the design of hydraulic infrastructure, such as dams, barrages, bridges, and irrigation, and flood control systems.
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