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Sara Martinez de Lizarrondo, Maxime Gauberti, Denis Vivien
Tuning the endogenous fibrinolytic system to prevent excessive thrombus formation is a tempting prophylactic strategy for thrombosis-related disorders [1]. However, we currently lack approved treatments able to induce a sustained hyperfibrinolytic state in humans. In this regard, valproic acid (VPA), a widely used antiepileptic drug, may be of clinical interest. Besides its still not fully understood antiepileptic properties, VPA is a class I selective histodeacetylase (HDAC) inhibitor and thus affects epigenetic regulation of gene expression [2]...
October 6, 2016: Journal of Thrombosis and Haemostasis: JTH
Oscar A Marcos-Contreras, Sara Martinez de Lizarrondo, Isabelle Bardou, Cyrille Orset, Mathilde Pruvost, Antoine Anfray, Yvann Frigout, Yannick Hommet, Laurent Lebouvier, Joan Montaner, Denis Vivien, Maxime Gauberti
Hyperfibrinolysis is a systemic condition occurring in various clinical disorders such as trauma, liver cirrhosis or leukemia. Apart from increased bleeding tendency, the pathophysiological consequences of hyperfibrinolysis remain largely unknown. Our present aim was to develop an experimental model of hyperfibrinolysis and to study its effects on the homeostasis of the blood brain barrier (BBB). We induced a sustained hyperfibrinolytic state in mice by hydrodynamic transfection of a plasmid encoding for tissue-type plasminogen activator (tPA)...
August 16, 2016: Blood
Cyrille Orset, Benoit Haelewyn, Stuart M Allan, Saema Ansar, Francesco Campos, Tae Hee Cho, Anne Durand, Mohamad El Amki, Marc Fatar, Isaac Garcia-Yébenes, Maxime Gauberti, Saskia Grudzenski, Ignacio Lizasoain, Eng Lo, Richard Macrez, Isabelle Margaill, Samaneh Maysami, Stephen Meairs, Norbert Nighoghossian, Josune Orbe, Jose Antonio Paramo, Jean-Jacques Parienti, Nancy J Rothwell, Marina Rubio, Christian Waeber, Alan R Young, Emmanuel Touzé, Denis Vivien
BACKGROUND AND PURPOSE: The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator. METHODS: We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery...
May 2016: Stroke; a Journal of Cerebral Circulation
Aurélien Briens, Maxime Gauberti, Jérôme Parcq, Joan Montaner, Denis Vivien, Sara Martinez de Lizarrondo
Cell-derived microparticles (MPs) are nano-sized vesicles released by activated cells in the extracellular milieu. They act as vectors of biological activity by carrying membrane-anchored and cytoplasmic constituents of the parental cells. Although detection and characterization of cell-derived MPs may be of high diagnostic and prognostic values in a number of human diseases, reliable measurement of their size, number and biological activity still remains challenging using currently available methods. In the present study, we developed a protocol to directly image and functionally characterize MPs using high-resolution laser-scanning confocal microscopy...
2016: Theranostics
Julie Belliere, Sara Martinez de Lizarrondo, Robin P Choudhury, Aurélien Quenault, Audrey Le Béhot, Christine Delage, Dominique Chauveau, Joost P Schanstra, Jean-Loup Bascands, Denis Vivien, Maxime Gauberti
Endothelial activation is a hallmark of cardiovascular diseases, acting either as a cause or a consequence of organ injury. To date, we lack suitable methods to measure endothelial activation in vivo. In the present study, we developed a magnetic resonance imaging (MRI) method allowing non-invasive endothelial activation mapping in the vasculature of the main organs affected during cardiovascular diseases. In clinically relevant contexts in mice (including systemic inflammation, acute and chronic kidney diseases, diabetes mellitus and normal aging), we provided evidence that this method allows detecting endothelial activation before any clinical manifestation of organ failure in the brain, kidney and heart with an exceptional sensitivity...
2015: Theranostics
Eloïse Lemarchand, Maxime Gauberti, Sara Martinez de Lizarrondo, Hélène Villain, Yohann Repessé, Axel Montagne, Denis Vivien, Carine Ali, Marina Rubio
BACKGROUND AND PURPOSE: Tissue-type plasminogen activator (tPA) is the only acute treatment for ischemic stroke. Unfortunately, the benefit of tPA-driven thrombolysis is not systematic, and understanding the reasons for this is mandatory. The balance between beneficial and detrimental effects of tPA might explain the limited overall efficiency of thrombolysis. Here, we investigated whether this balance could be influenced by excessive alcohol intake. METHODS: We used a murine model of thromboembolic stroke, coupled to an array of biochemical assays, near-infrared or magnetic resonance imaging scans, 2-photon microscopy, hydrodynamic transfections, and immunohistological techniques...
June 2015: Stroke; a Journal of Cerebral Circulation
Morteza Mahmoudi, Sara Sheibani, Abbas S Milani, Farhad Rezaee, Maxime Gauberti, Rassoul Dinarvand, Hojatollah Vali
AIMS: We aimed to investigate the physicochemical effects of superparamagnetic iron oxide nanoparticles (SPIONs) on the composition of the protein corona and their correspondence toxicological issues. MATERIALS & METHODS: SPIONs of different sizes and surface charges were exposed to fetal bovine serum. The structure/composition and biological effects of the protein corona-SPION complexes were probed. RESULTS & DISCUSSION: The affinity and level of adsorption of specific proteins is strongly dependent on the size and surface charge of the SPIONs...
January 2015: Nanomedicine
Maxime Gauberti, Axel Montagne, Aurélien Quenault, Denis Vivien
Although the blood-brain barrier (BBB) was thought to protect the brain from the effects of the immune system, immune cells can nevertheless migrate from the blood to the brain, either as a cause or as a consequence of central nervous system (CNS) diseases, thus contributing to their evolution and outcome. Accordingly, as the interface between the CNS and the peripheral immune system, the BBB is critical during neuroinflammatory processes. In particular, endothelial cells are involved in the brain response to systemic or local inflammatory stimuli by regulating the cellular movement between the circulation and the brain parenchyma...
2014: Frontiers in Cellular Neuroscience
Thomas Gaberel, Clement Gakuba, Romain Goulay, Sara Martinez De Lizarrondo, Jean-Luc Hanouz, Evelyne Emery, Emmanuel Touze, Denis Vivien, Maxime Gauberti
BACKGROUND AND PURPOSE: The aim of the present study was to investigate the impact of different stroke subtypes on the glymphatic system using MRI. METHODS: We first improved and characterized an in vivo protocol to measure the perfusion of the glymphatic system using MRI after minimally invasive injection of a gadolinium chelate within the cisterna magna. Then, the integrity of the glymphatic system was evaluated in 4 stroke models in mice including subarachnoid hemorrhage (SAH), intracerebral hemorrhage, carotid ligature, and embolic ischemic stroke...
October 2014: Stroke; a Journal of Cerebral Circulation
Thomas Gaberel, Axel Montagne, Flavie Lesept, Maxime Gauberti, Eloïse Lemarchand, Cyrille Orset, Romain Goulay, Thomas Bertrand, Evelyne Emery, Denis Vivien
Intraventricular hemorrhage (IVH) is the most severe form of stroke with intraventricular fibrinolysis (IVF) as a hopeful treatment. Urokinase (uPA) and tissue-type plasminogen activator (tPA) are used for IVF in Human. No clinical trial has evaluated the differential impact of these two fibrinolytics for IVF. Thus, we decided here to compare the use of these two fibrinolytics in a pre-clinical study. IVH was induced in rats by injection of collagenase type VII within the brain parenchyma followed by an IVF...
October 2014: Neuropharmacology
Sighild Lemarchant, Mathilde Pruvost, Marie Hébert, Maxime Gauberti, Yannick Hommet, Aurélien Briens, Eric Maubert, Yatma Gueye, François Féron, Didier Petite, Marcel Mersel, Jean-Claude do Rego, Hubert Vaudry, Jari Koistinaho, Carine Ali, Véronique Agin, Evelyne Emery, Denis Vivien
Although tissue plasminogen activator (tPA) is known to promote neuronal remodeling in the CNS, no mechanism of how this plastic function takes place has been reported so far. We provide here in vitro and in vivo demonstrations that this serine protease neutralizes inhibitory chondroitin sulfate proteoglycans (CSPGs) by promoting their degradation via the direct activation of endogenous type 4 disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4). Accordingly, in a model of compression-induced spinal cord injury (SCI) in rats, we found that administration of either tPA or its downstream effector ADAMTS-4 restores the tPA-dependent activity lost after the SCI and thereby, reduces content of CSPGs in the spinal cord, a cascade of events leading to an improved axonal regeneration/sprouting and eventually long term functional recovery...
June 2014: Neurobiology of Disease
Audrey Le Behot, Maxime Gauberti, Sara Martinez De Lizarrondo, Axel Montagne, Eloïse Lemarchand, Yohann Repesse, Sylvain Guillou, Cécile V Denis, Eric Maubert, Cyrille Orset, Denis Vivien
Interactions between platelet glycoprotein (Gp) IIb/IIIa and plasma proteins mediate platelet cross-linking in arterial thrombi. However, GpIIb/IIIa inhibitors fail to disperse platelet aggregates after myocardial infarction or ischemic stroke. These results suggest that stability of occlusive thrombi involves additional and as-yet-unidentified mechanisms. In the present study, we investigated the mechanisms driving platelet cross-linking during occlusive thrombus formation. Using computational fluid dynamic simulations and in vivo thrombosis models, we demonstrated that the inner structure of occlusive thrombi is heterogeneous and primarily determined by the rheological conditions that prevailed during thrombus growth...
May 22, 2014: Blood
M Gauberti, S Martinez de Lizarrondo, C Orset, D Vivien
BACKGROUND: Secondary microthrombosis is a major pathophysiologic mechanism leading to brain damage following transient mechanical vascular occlusion (TMVO), the most widely used experimental stroke model. Whether secondary microthrombosis also occurs in non-TMVO stroke models represents an important issue for clinical translation of antimicrothrombosis therapeutic strategies. OBJECTIVES: To assess the occurrence and the pathogenic role of secondary microthrombosis in two thrombin-induced stroke models in mice and non-human primates (Macaca mulatta)...
2014: Journal of Thrombosis and Haemostasis: JTH
Thomas Gaberel, Clement Gakuba, Marie Hebert, Axel Montagne, Veronique Agin, Marina Rubio, Evelyne Emery, Denis Vivien, Maxime Gauberti
BACKGROUND AND PURPOSE: The aim of the present study was to investigate the effects of normobaric oxygen (NBO) therapy on T2*-weighted images of intracranial hemorrhages (ICHs). METHODS: Two common models of ICH were performed in mice, and longitudinal T2*-weighted images of the hematomas were acquired under normoxia or NBO. The effects of NBO were also investigated on perfusion-weighted imaging, susceptibility-weighted imaging, and molecular imaging of vascular cell adhesion molecule-1 after ICH...
December 2013: Stroke; a Journal of Cerebral Circulation
Maxime Gauberti, Axel Montagne, Oscar A Marcos-Contreras, Audrey Le Béhot, Eric Maubert, Denis Vivien
BACKGROUND AND PURPOSE: Our aim was to assess the spatiotemporal evolution of the cerebrovascular inflammation occurring after ischemic and hemorrhagic strokes using a recently developed, fast, and ultra-sensitive molecular MRI method. METHODS: We first assessed longitudinally the cerebrovascular inflammation triggered by collagenase-induced hemorrhage and by permanent/transient middle cerebral artery occlusion in mice, using MRI after injection of microparticles of iron oxide targeted to vascular cell adhesion molecule-1 (MPIOs-αVCAM-1)...
July 2013: Stroke; a Journal of Cerebral Circulation
Anne Mayeur, Célia Duclos, Axel Honoré, Maxime Gauberti, Laurent Drouot, Jean-Claude do Rego, Nicolas Bon-Mardion, Laetitia Jean, Eric Vérin, Evelyne Emery, Sighild Lemarchant, Denis Vivien, Olivier Boyer, Jean-Paul Marie, Nicolas Guérout
Spinal cord injury (SCI) induces a permanent disability in patients. To this day no curative treatment can be proposed to restore lost functions. Therefore, extensive experimental studies have been conducted to induce recovery after SCI. One of the most promising therapies is based on the use of olfactory ensheathing cells (OECs). OECs can be obtained from either the olfactory bulbs (OB-OECs) or from olfactory mucosa (OM-OECs), involving a less invasive approach for autotransplantation. However the vast majority of experimental transplantations have been focusing on OB-OECs although the OM represents a more accessible source of OECs...
2013: PloS One
Thomas Gaberel, Richard Macrez, Maxime Gauberti, Axel Montagne, Marie Hebert, Karl-Uwe Petersen, Emmanuel Touze, Véronique Agin, Evelyne Emery, Carine Ali, Denis Vivien
Ischemic and hemorrhagic strokes have different etiologies, but share some pathogenic mechanisms, including a pro-neurotoxic effect of endogenous tissue plasminogen activator (tPA) via N-methyl-d-Aspartate (NMDA) receptors. Thus, in a model of intracerebral hemorrhage in rats, we investigated the therapeutic value of a strategy of immunotherapy (αATD-GluN1 antibody) preventing the interaction of tPA with NMDA receptors. We found that a single intravenous injection of αATD-GluN1 reduced brain edema, neuronal death, microglial activation and functional deficits following intracerebral hemorrhage, without affecting the hematoma volume...
April 2013: Neuropharmacology
Axel Montagne, Marie Hébert, Amandine Jullienne, Flavie Lesept, Audrey Le Béhot, Morgane Louessard, Maxime Gauberti, Cyrille Orset, Carine Ali, Véronique Agin, Eric Maubert, Denis Vivien
BACKGROUND AND PURPOSE: Despite side effects including N-methyl-d-aspartate-mediated neurotoxicity, recombinant tissue-type plasminogen activator (rtPA) remains the only approved acute treatment for ischemic stroke. Memantine, used for treatment of Alzheimer disease, is an antagonist for N-methyl-d-aspartate receptors. We investigated whether memantine could be used as a neuroprotective adjunct therapy for rtPA-induced thrombolysis after stroke. METHODS: In vitro N-methyl-d-aspartate exposure, oxygen and glucose deprivation, and N-methyl-d-aspartate-mediated calcium videomicroscopy experiments were performed on murine cortical neurons in the presence of rtPA and memantine...
October 2012: Stroke; a Journal of Cerebral Circulation
Axel Montagne, Maxime Gauberti, Richard Macrez, Amandine Jullienne, Aurélien Briens, Jean-Sébastien Raynaud, Gaelle Louin, Alain Buisson, Benoit Haelewyn, Fabian Docagne, Gilles Defer, Denis Vivien, Eric Maubert
Since endothelial cells can be targeted by large contrast-carrying particles, molecular imaging of cerebrovascular cell activation is highly promising to evaluate the underlying inflammation of the central nervous system (CNS). In this study, we aimed to demonstrate that molecular magnetic resonance imaging (MRI) of cerebrovascular cell activation can reveal CNS disorders in the absence of visible lesions and symptoms. To this aim, we optimized contrast carrying particles targeting vascular cell adhesion molecule-1 and MRI protocols through both in vitro and in vivo experiments...
November 1, 2012: NeuroImage
M Letourneux, B Clin-Godard, M-F Marquignon, P Gauberti
As long as the value of screening for cancers related to asbestos is not proven in the population at risk, the medical benefits of follow-up post-professional exposure remain uncertain and the only justification is to answer the questions of anxious retired workers concerning the consequences of their past-exposure and to provide compensation for any abnormalities that are demonstrated. In this country, to answer the questions posed in the title of this contribution in the case of pathologies related to asbestos, it is necessary, after verifying the fact and the level of exposure, to identify the pleural or pulmonary fibrosis and, above all, the pleural plaques, which constitute the essential lesions currently screened for...
February 2012: Revue des Maladies Respiratoires
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