Les interfaces sang-cerveau comme la barrière hémato-encéphalique (BHE), les plexus choroïdes (PC) ou les organes circumventriculaires (OCV), constituent des barrières physiologiques nécessaires au fonctionnement du système nerveux central. Ces barrières sont à la fois « physiques », constituées de jonctions serrées, et « enzymatiques ». Longtemps considérées comme immatures chez le fœtus, ces barrières sont en réalité présentes précocement au cours du développement. Leurs caractéristiques et leurs propriétés restent peu connues chez l'homme. Nos travaux montrent que les PC expriment, précocement au cours du développement, des protéines de jonction serrée, les claudines (CLDN) 1, 2 et 3 chez le rat et chez l'homme. Cette expression est dynamique au cours du développement avec une apparition progressive de la CLDN2 pouvant avoir un lien avec la sécrétion du liquide céphalo-rachidien. Les CLDN 1 et 3 sont identifiées chez le fœtus humain au niveau de l'organe sous-commissural (OSC), un des OCV. La CLDN5 est exprimée précocement au niveau de la BHE chez le rat et chez l'homme et son expression est altérée dans un modèle d'excitotoxicité néonatale. Nos travaux montrent également que l'analyse du profil des CLDN est utile en pathologie tumorale notamment dans la compréhension et le diagnostic de tumeurs développées à partir des PC ou de l'OSC. Enfin, diverses enzymes antioxydantes et de détoxification dont l'époxyde hydrolase microsomale sont exprimées à 22 semaines d'aménorrhée principalement au niveau des PC du fœtus humain. Ces données suggèrent des capacités de détoxification des PC, d'installation précoce au cours du développement chez l'homme / Blood-brain interfaces including blood-brain barrier (BBB), choroid plexuses (CP) or circumventricular organs (CVO) are physiological barriers required for brain homeostasis. These barriers are “physical”, with tight junctions, and “enzymatic”. Though long considered immature in fetuses, these barriers are present from an early stage of development. Their characteristics and their properties are largely unknown in humans. Our work demonstrates that CP express tight junction-associated proteins claudins (CLDN) 1, 2, and 3 at early stages of development in rat and human. This expression is dynamic during development as shown by the progressive increase of CLDN2 immunopositivity that may follow increase in cerebrospinal fluid secretion. CLDN 1 and 3 are identified in human fetal subcommissural organ (SCO), one of the CVO. CLDN5 is early expressed in rat and human BBB and its expression is disrupted by excitotoxic injury. Our work also shows that CLDN immunohistochemical profile is useful in tumoral pathology, notably to better understand and diagnose tumors arising from CP or the SCO. Finally, various antioxidant and detoxifying enzymes such as the microsomal epoxide hydrolase are expressed at 22 weeks of gestation in the human fetus, mainly in CP. These results suggest a high detoxifying capacity for the CP during development in humans

<p>The ß-carbolines norharman and harman structurally resemble the synthetic compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that is known for its ability to damage neuromelanin-containing dopaminergic neurons of the substantia nigra and thereby induce parkinsonism. MPTP is, however, not normally present in the environment whereas the ß-carbolines are present in cooked food and tobacco smoke. </p><p>In this thesis it was demonstrated that norharman and harman had affinity to melanin and were retained in neuromelanin-containing neurons of frogs up to 30 days post-injection (the longest survival time examined). It was also demonstrated that norharman induced neurodegeneration, activation of glia cells and motor impairment in mice. Furthermore, this compound induced ER stress and cell death in PC12 cells. An in vitro model of dopamine melanin-loaded PC12 cells was developed in order to study the effect of melanin on norharman-induced toxicity. In this model, melanin seemed to attenuate toxicity induced by low concentrations of norharman. After exposure to the highest concentration of norharman, melanin clusters were disaggregated and there was an increased expression of stress proteins and caspases-3, known to be involved in apoptosis.</p><p>The polycyclic aromatic hydrocarbon, 7,12-dimethylbenz[<i>a</i>]anthracene was demonstrated to have a CYP1A1-dependent localization in endothelial cells in the choroid plexus, in the veins in the leptomeninges and in the cerebral veins of mice pre-treated with CYP1-inducers. </p><p>These results demonstrate that the distribution of environmental compounds could be influenced by the presence of neuromelanin and expression of CYP enzymes in the brain and that norharman may induce neurotoxic effects in vivo and in vitro.</p>

The ß-carbolines norharman and harman structurally resemble the synthetic compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that is known for its ability to damage neuromelanin-containing dopaminergic neurons of the substantia nigra and thereby induce parkinsonism. MPTP is, however, not normally present in the environment whereas the ß-carbolines are present in cooked food and tobacco smoke. In this thesis it was demonstrated that norharman and harman had affinity to melanin and were retained in neuromelanin-containing neurons of frogs up to 30 days post-injection (the longest survival time examined). It was also demonstrated that norharman induced neurodegeneration, activation of glia cells and motor impairment in mice. Furthermore, this compound induced ER stress and cell death in PC12 cells. An in vitro model of dopamine melanin-loaded PC12 cells was developed in order to study the effect of melanin on norharman-induced toxicity. In this model, melanin seemed to attenuate toxicity induced by low concentrations of norharman. After exposure to the highest concentration of norharman, melanin clusters were disaggregated and there was an increased expression of stress proteins and caspases-3, known to be involved in apoptosis. The polycyclic aromatic hydrocarbon, 7,12-dimethylbenz[a]anthracene was demonstrated to have a CYP1A1-dependent localization in endothelial cells in the choroid plexus, in the veins in the leptomeninges and in the cerebral veins of mice pre-treated with CYP1-inducers. These results demonstrate that the distribution of environmental compounds could be influenced by the presence of neuromelanin and expression of CYP enzymes in the brain and that norharman may induce neurotoxic effects in vivo and in vitro.