Blood-brain barrier disruption with focused ultrasound enhances delivery of dopamine transporter tracer (PE2I) into the brain

International audiencePE2I is one of the most selective ligands for dopamine transporter. However it is associated with blood-brain barrier (BBB) permeability limitations. The aim of this study was to investigate the use of ultrasound and microbubbles to increase its delivery through the BBB and by determining the optimal experimental conditions that achieve a transient and safe BBB disruption. First, we stablished the ultrasound conditions that achieved a transient BBB disruption in rats using a non-permeant marker, Evans blue. Hence SonoVue® (450μL/kg) and Evans blue (100mg/kg) were intravenously administered. BBB leakage was obtained using ultrasound insonation through the rat skull at 1.6MPa, PRF 1Hz, duty cycle 1%, burst 10ms during 120sec. BBB disruption was observed in all treated animals (N=4) by histological analysis. The same experimental conditions were applied to enhance brain uptake of PE2I. Biological samples were analyzed using a scintillation counter apparatus. The results showed 50% and 20% increase of 125I-PE2I uptake in the striatum and cerebral cortex, respectively, in the treated rats (N=5) versus control (N=4). Similar enhancements were observed using SonoVue® at half concentration. This innovative method provides a great potential for intracerebral delivery of molecular ligands that could be used for the therapy of brain diseases

Regional characterization of energy metabolism in the brain of normal and MPTP-intoxicated mice using new markers of glucose and phosphate transport

The gibbon ape leukemia virus (GALV), the amphotropic murine leukemia virus (AMLV) and the human T-cell leukemia virus (HTLV) are retroviruses that specifically bind nutrient transporters with their envelope glycoproteins (Env) when entering host cells. Here, we used tagged ligands derived from GALV, AMLV, and HTLV Env to monitor the distribution of their cognate receptors, the inorganic phosphate transporters PiT1 and PiT2, and the glucose transporter GLUT1, respectively, in basal conditions and after acute energy deficiency. For this purpose, we monitored changes in the distribution of PiT1, PiT2 and GLUT1 in the cerebellum, the frontal cortex, the corpus callosum, the striatum and the substantia nigra (SN) of C57/BL6 mice after administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridinium (MPTP), a mitochondrial complex I inhibitor which induces neuronal degeneration in the striato-nigral network

Plan de déplacements pour les lieux d'activités : exemple du CETE Nord-Picardie

Dans un contexte de suppression d'un millier de places de stationnement dans le quartier, le Centre d'études techniques de l'Equipement (CETE) Nord-Picardie - situé au centre de Lille et bénéficiant d'une bonne desserte multimodale - a engagé une démarche de plan de déplacements (PDE) pour accompagner le changement d'habitudes de déplacements domicile-travail des salariés.L'élaboration du PDE - inspirée des démarches de gestion de projet - a été menée en moins d'un an, en s'appuyant sur cette opportunité d'un changement des pratiques de déplacements domicile-travail et sur un environnement partenariat favorable.Outre la situation géographique du site et la requalification de la place principale du quartier conduisant à la suppression du stationnement gratuit, la démarche de PDE a bénéficié d'une mobilité domicile-travail caractéristique des salariés des villes centres : 51% des agents du CETE venaient en voiture, 18% en train, 19% à pied ou à vélo, 12% en autobus, métro ou tramway.Les phases du projet se sont déroulées autour des objectifs suivants : sensibiliser les agents et la structure organisationnelle à la prise en compte de la problématique des déplacements urbains au cours de la phase de diagnostic ; élaborer un plan d'actions PDE en créant les conditions nécessaires à une mobilisation collective, afin d'aboutir à un véritable projet d'entreprise. De nombreux outils d'actions et de sensibilisation ont été utilisés : diagnostic déplacements avec l'élaboration de cartes d'accessibilité (isochrones) et du budget déplacement du CETE, enquête autoadmimistrée par questionnaire, journaux de bord hebdomadaires, entretiens semi-directifs, observations des pratiques dans la cour intérieure, micro-trottoirs, site Intranet PDE et courriels ciblés, animation autour de la journée "En ville, sans ma voiture !", etc.Ce rapport permet de capitaliser les enseignements de la méthode d'élaboration du diagnostic et de la phase de sensibilisation des salariés autour du projet, en particulier concernant les facteurs de mobilisation collective au sein de la structure et de sensibilisation individuelle des employés

Inflammatory process in Parkinson disease: neuroprotection by neuropeptide Y

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Modification of dopamine neurotransmission in the nucleus accumbens of rats deficient in n-3 polyunsaturated fatty acids

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Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat

International audienceWe explored the effects of chronic alpha-linolenic acid dietary deficiency on serotoninergic neurotransmission. In vivo synaptic serotonin (5-HT) levels were studied in basal and pharmacologically stimulated conditions using intracerebral microdialysis in the hippocampus of awake 2-month-old rats. We also studied the effects of reversion of the deficient diet on fatty acid composition and serotoninergic neurotransmission. A balanced (control) diet was supplied to deficient rats at different stages of development, i.e. from birth, 7, 14 or 21 days of age. We demonstrated that chronic n-3 polyunsaturated fatty acid dietary deficiency induced changes in the synaptic levels of 5-HT both in basal conditions and after pharmacological stimulation with fenfluramine. Higher levels of basal 5-HT release and lower levels of 5-HT-stimulated release were found in deficient than in control rats. These neurochemical modifications were reversed by supply of the balanced diet provided at birth or during the first 2 weeks of life through the maternal milk, whereas they persisted if the balanced diet was given from weaning (at 3 weeks of age). This suggests that provision of essential fatty acids is durably able to affect brain function and that this is related to the developmental stage during which the deficiency occurs

Oxidative Stress Is Related to the Deleterious Effects of Heme Oxygenase-1 in an In Vivo Neuroinflammatory Rat Model

Heme oxygenase-1 (HO-1) induction is associated with beneficial or deleterious effects depending on the experimental conditions adopted and the neurodegenerative rodent models used. The present study aimed first to evaluate the effects of cerebral HO-1 induction in an in vivo rat model of neuroinflammation by intrastriatal injection of quinolinic acid (QA) and secondly to explore the role played by reactive oxygen species (ROS) and free iron (Fe2+) derived from heme catabolism promoted by HO-1. Chronic I.P. treatment with the HO-1 inductor and substrate hemin was responsible for a significant dose-related increase of cerebral HO-1 production. Brain tissue loss, microglial activation, and neuronal death were significantly higher in rats receiving QA plus hemin (H-QA) versus QA and controls. Significant increase of ROS production in H-QA rat brain was inhibited by the specific HO-1 inhibitor ZnPP which supports the idea that ROS level augmentation in hemin-treated animals is a direct consequence of HO-1 induction. The cerebral tissue loss and ROS level in hemin-treated rats receiving the iron chelator deferoxamine were significantly decreased, demonstrating the involvement of Fe2+in brain ROS production. Therefore, the deleterious effects of HO-1 expression in this in vivo neuroinflammatory model were linked to a hyperproduction of ROS, itself promoted by free iron liberation

Alpha-7 nicotinic acetylcholine receptor agonist treatment in a rat model of Huntington's disease and involvement of heme oxygenase-1

Neuroinflammation is a common element involved in the pathophysiology of neurodegenerative diseases. We recently reported that repeated alpha-7 nicotinic acetylcholine receptor (α7nAChR) activations by a potent agonist such as PHA 543613 in quinolinic acid-injured rats exhibited protective effects on neurons. To further investigate the underlying mechanism, we established rat models of early-stage Huntington's disease by injection of quinolinic acid into the right striatum and then intraperitoneally injected 12 mg/kg PHA 543613 or sterile water, twice a day during 4 days. Western blot assay results showed that the expression of heme oxygenase-1 (HO-1), the key component of the cholinergic anti-inflammatory pathway, in the right striatum of rat models of Huntington's disease subjected to intraperitoneal injection of PHA 543613 for 4 days was significantly increased compared to the control rats receiving intraperitoneal injection of sterile water, and that the increase in HO-1 expression was independent of change in α7nAChR expression. These findings suggest that HO-1 expression is unrelated to α7nAChR density and the increase in HO-1 expression likely contributes to α7nAChR activation-related neuroprotective effect in early-stage Huntington's disease