ADAMTS proteoglycanases in the physiological and pathological central nervous system

ADAMTS-1, -4, -5 and -9 belong to ‘a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)’ family and more precisely to the proteoglycanases subgroup based on their common ability to degrade chondroitin sulfate proteoglycans. They have been extensively investigated for their involvement in inflammation-induced osteoarthritis, and a growing body of evidence indicates that they may be of key importance in the physiological and pathological central nervous system (CNS). In this review, we discuss the deregulated expression of ADAMTS proteoglycanases during acute CNS injuries, such as stroke and spinal cord injury. Then, we provide new insights on ADAMTS proteoglycanases mediating synaptic plasticity, neurorepair, angiogenesis and inflammation mechanisms. Altogether, this review allows us to propose that ADAMTS proteoglycanases may be original therapeutic targets for CNS injuries.This work was supported by the University of Eastern Finland and the ERANET-Neuron research program ‘ProteA: Proteases before, during and after stroke’, 2012–2015.Peer Reviewe

Oligodendroglial Epigenetics, from Lineage Specification to Activity-Dependent Myelination

Oligodendroglial cells are the myelinating cells of the central nervous system. While myelination is crucial to axonal activity and conduction, oligodendrocyte progenitor cells and oligodendrocytes have also been shown to be essential for neuronal support and metabolism. Thus, a tight regulation of oligodendroglial cell specification, proliferation, and myelination is required for correct neuronal connectivity and function. Here, we review the role of epigenetic modifications in oligodendroglial lineage cells. First, we briefly describe the epigenetic modalities of gene regulation, which are known to have a role in oligodendroglial cells. We then address how epigenetic enzymes and/or marks have been associated with oligodendrocyte progenitor specification, survival and proliferation, differentiation, and finally, myelination. We finally mention how environmental cues, in particular, neuronal signals, are translated into epigenetic modifications, which can directly influence oligodendroglial biology

ADAMTS proteoglycanases in the physiological and pathological central nervous system.

International audience: ADAMTS-1, -4, -5 and -9 belong to 'a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)' family and more precisely to the proteoglycanases subgroup based on their common ability to degrade chondroitin sulfate proteoglycans. They have been extensively investigated for their involvement in inflammation-induced osteoarthritis, and a growing body of evidence indicates that they may be of key importance in the physiological and pathological central nervous system (CNS). In this review, we discuss the deregulated expression of ADAMTS proteoglycanases during acute CNS injuries, such as stroke and spinal cord injury. Then, we provide new insights on ADAMTS proteoglycanases mediating synaptic plasticity, neurorepair, angiogenesis and inflammation mechanisms. Altogether, this review allows us to propose that ADAMTS proteoglycanases may be original therapeutic targets for CNS injuries

and pathological central nervous system

ADAMTS-1,-4,-5 and-9 belong to ‘a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)’ family and more precisely to the proteoglycanases subgroup based on their common ability to degrade chondroitin sulfate proteoglycans. They have been extensively investigated for their involvement in inflammation-induced osteoarthritis, and a growing body of evidence indicates that they may be of key importance in the physiological and pathological central nervous system (CNS). In this review, we discuss the deregulated expression of ADAMTS proteoglycanases during acute CNS injuries, such as stroke and spinal cord injury. Then, we provide new insights on ADAMTS proteoglycanases mediating synaptic plasticity, neurorepair, angiogenesis and inflammation mechanisms. Altogether, this review allows us to propose that ADAMTS proteoglycanases may be original therapeutic targets for CNS injuries

In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel

A recently developed inhibitor of retrograde transport, namely Retro-2.1, proved to be a potent and broad-spectrum lead in vitro against intracellular pathogens, such as toxins, parasites, intracellular bacteria and viruses. To circumvent its low aqueous solubility, a formulation in poly(ethylene glycol)-block-poly(D,L)lactide micelle nanoparticles was developed. This formulation enabled the study of the pharmacokinetic parameters of Retro-2.1 in mice following intravenous and intraperitoneal injections, revealing a short blood circulation time, with an elimination half-life of 5 and 6.7 h, respectively. To explain the poor pharmacokinetic parameters, the metabolic stability of Retro-2.1 was studied in vitro and in vivo, revealing fast cytochrome-P-450-mediated metabolism into a less potent hydroxylated analogue. Subcutaneous injection of Retro-2.1 formulated in a biocompatible and bioresorbable polymer-based thermosensitive hydrogel allowed for sustained release of the drug, with an elimination half-life of 19 h, and better control of its metabolism. This study provides a guideline on how to administer this promising lead in vivo in order to study its efficacy

Subcutaneous administration of the retrograde transport inhibitor Retro-2.1 formulated in a PLGA-PEG-PLGA thermosensitive hydrogel leads to a sustained release of the drug and a better control of its metabolism in vivo

A recently developed inhibitor of the retrograde transport, namely Retro-2.1, proved to be a potent and broad-spectrum lead in vitro against intracellular pathogens such as toxins, parasites, intracellular bacteria, and viruses. In order to circumvent its low aqueous solubility, a formulation in poly(ethylene glycol)-bloc-poly(D,L)lactide micelles was developed. This formulation allowed studying Retro-2.1 pharmacokinetic parameters in mice following intravenous or intraperitoneal injection, revealing a low blood circulation time. To explain these poor pharmacokinetic parameters, Retro-2.1 metabolic stability was studied in vitro and in vivo revealing a fast cytochrome P-450-mediated metabolism into a less potent hydroxylated analog. Subcutaneous injection of Retro-2.1 formulated in a biocompatible and bioresorbable polymer-based thermosensitive hydrogel allowed for a sustained-release of the drug and a better control of its metabolism. This study gives a guideline on how to administer this promising lead in vivo in order to study its efficacy

Extracellular Matrix Modulation Is Driven by Experience-Dependent Plasticity During Stroke Recovery

Following stroke, complete cellular death in the ischemic brain area may ensue, with remaining brain areas undergoing tissue remodelling to various degrees. Experience-dependent brain plasticity exerted through an enriched environment (EE) promotes remodelling after central nervous system injury, such as stroke. Post-stroke tissue reorganization is modulated by growth inhibitory molecules differentially expressed within the ischemic hemisphere, like chondroitin sulfate proteoglycans found in perineuronal nets (PNNs). PNNs in the neocortex predominantly enwrap parvalbumin-containing GABAergic (PV/GABA) neurons, important in sensori-information processing. Here, we investigate how extracellular matrix (ECM) proteases and their inhibitors may participate in the regulation of PNN integrity during stroke recovery. Rats were subjected to photothrombotic stroke in the motor cortex, and functional deficits were assessed at 7 days of recovery. Sham and stroked rats were housed in either standard or EE conditions for 5 days, and infarct volumes were calculated. PNNs were visualized by immunohistochemistry and counted in the somatosensory cortex of both hemispheres. mRNA expression levels of ECM proteases and protease inhibitors were assessed by RT-qPCR and their activity analyzed by gel zymography. PNNs and protease activity were also studied in brains from stroke patients where similar results were observed. EE starting 2 days after stroke and continuing for 5 days stimulated behavioral recovery of limb-placement ability without affecting infarct size. EE promoted a decrease of PNNs around PV/GABA neurons and a concomitant modulation of the proteolytic activity and mRNA expression of ECM proteases and protease inhibitors in the somatosensory cortex. This study provides molecular targets for novel therapies that could support rehabilitation of stroke patients

Habiter

On assiste actuellement à l'émergence d’une variété d’initiatives d’habitat animées par une volonté d’habiter différemment et peut être même de vivre autrement. Celles-ci se fédèrent autour de projets, d’associations, de regroupements de personnes affirmant des revendications fondées notamment sur une volonté de recréer du lien social, un mode de vie spécifique, une conscience écologique, une participation à son cadre de vie, voire une volonté de s’inscrire plus activement dans la vie de la cité… Les choix d’action varient. Ces initiatives s’inscrivent ainsi dans un contexte socio-économique particulier qui semble faire émerger des attentes et des besoins en matière d’habiter qu’il ne peut satisfaire. Quelles interprétations donner à cet élan vers un habitat plus communautaire ? À partir de contributions révélant diverses formes d’expériences d’habiter contemporaines, l’objet de ce numéro interroge les parcours mais aussi les motivations, formes d’engagement, valeurs sous-jacentes qui fondent ces dynamiques et ce qu’elles peuvent révéler comme regard critique de l’évolution contemporaine