Prostaglandin E2 metabolism in rat brain: Role of the blood-brain interfaces

<p>Abstract</p> <p>Background</p> <p>Prostaglandin E₂(PGE₂) is involved in the regulation of synaptic activity and plasticity, and in brain maturation. It is also an important mediator of the central response to inflammatory challenges. The aim of this study was to evaluate the ability of the tissues forming the blood-brain interfaces to act as signal termination sites for PGE₂by metabolic inactivation.</p> <p>Methods</p> <p>The specific activity of 15-hydroxyprostaglandin dehydrogenase was measured in homogenates of microvessels, choroid plexuses and cerebral cortex isolated from postnatal and adult rat brain, and compared to the activity measured in peripheral organs which are established signal termination sites for prostaglandins. PGE₂metabolites produced <it>ex vivo </it>by choroid plexuses were identified and quantified by HPLC coupled to radiochemical detection.</p> <p>Results</p> <p>The data confirmed the absence of metabolic activity in brain parenchyma, and showed that no detectable activity was associated with brain microvessels forming the blood-brain barrier. By contrast, 15-hydroxyprostaglandin dehydrogenase activity was measured in both fourth and lateral ventricle choroid plexuses from 2-day-old rats, albeit at a lower level than in lung or kidney. The activity was barely detectable in adult choroidal tissue. Metabolic profiles indicated that isolated choroid plexus has the ability to metabolize PGE₂, mainly into 13,14-dihydro-15-keto-PGE₂. In short-term incubations, this metabolite distributed in the tissue rather than in the external medium, suggesting its release in the choroidal stroma.</p> <p>Conclusion</p> <p>The rat choroidal tissue has a significant ability to metabolize PGE₂during early postnatal life. This metabolic activity may participate in signal termination of centrally released PGE₂in the brain, or function as an enzymatic barrier acting to maintain PGE₂homeostasis in CSF during the critical early postnatal period of brain development.</p

Transport and Metabolism at Blood–Brain Interfaces and in Neural Cells: Relevance to Bilirubin-Induced Encephalopathy

Bilirubin, the end-product of heme catabolism, circulates in non-pathological plasma mostly as a protein-bound species. When bilirubin concentration builds up, the free fraction of the molecule increases. Unbound bilirubin then diffuses across blood–brain interfaces (BBIs) into the brain, where it accumulates and exerts neurotoxic effects. In this classical view of bilirubin neurotoxicity, BBIs act merely as structural barriers impeding the penetration of the pigment-bound carrier protein, and neural cells are considered as passive targets of its toxicity. Yet, the role of BBIs in the occurrence of bilirubin encephalopathy appears more complex than being simple barriers to the diffusion of bilirubin, and neural cells such as astrocytes and neurons can play an active role in controlling the balance between the neuroprotective and neurotoxic effects of bilirubin. This article reviews the emerging in vivo and in vitro data showing that transport and metabolic detoxification mechanisms at the blood–brain and blood–cerebrospinal fluid barriers may modulate bilirubin flux across both cellular interfaces, and that these protective functions can be affected in chronic unconjugated hyperbilirubinemia. Then the in vivo and in vitro arguments in favor of the physiological antioxidant function of intracerebral bilirubin are presented, as well as the potential role of transporters such as ABCC1 and metabolizing enzymes such as cytochromes P-450 in setting the cerebral cell- and structure-specific toxicity of bilirubin following hyperbilirubinemia. The relevance of these data to the pathophysiology of bilirubin-induced neurological diseases is discussed

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease.

The barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the choroid plexuses. At the interface between two circulating fluids, these richly vascularized veil-like structures display a peculiar morphology explained by their developmental origin, and fulfill several functions essential for CNS homeostasis. They form a neuroprotective barrier preventing the accumulation of noxious compounds into the CSF and brain, and secrete CSF, which participates in the maintenance of a stable CNS internal environment. The CSF circulation plays an important role in volume transmission within the developing and adult brain, and CSF compartments are key to the immune surveillance of the CNS. In these contexts, the choroid plexuses are an important source of biologically active molecules involved in brain development, stem cell proliferation and differentiation, and brain repair. By sensing both physiological changes in brain homeostasis and peripheral or central insults such as inflammation, they also act as sentinels for the CNS. Finally, their role in the control of immune cell traffic between the blood and the CSF confers on the choroid plexuses a function in neuroimmune regulation and implicates them in neuroinflammation. The choroid plexuses, therefore, deserve more attention while investigating the pathophysiology of CNS diseases and related comorbidities

Vascular network expansion, integrity of blood–brain interfaces, and cerebrospinal fluid cytokine concentration during postnatal development in the normal and jaundiced rat

Background: Severe neonatal jaundice resulting from elevated levels of unconjugated bilirubin in the blood induces dramatic neurological impairment. Central oxidative stress and an inflammatory response have been associated with the pathophysiological mechanism. Cells forming the blood–brain barrier and the choroidal blood–CSF barrier are the first CNS cells exposed to increased plasma levels of unconjugated bilirubin. These barriers are key regulators of brain homeostasis and require active oxidative metabolism to fulfill their protective functions. The choroid plexus-CSF system is involved in neuroinflammatory processes. In this paper, we address the impact of neonatal hyperbilirubinemia on some aspects of brain barriers. We describe physiological changes in the neurovascular network, blood–brain/CSF barriers integrities, and CSF cytokine levels during the postnatal period in normobilirubinemic animals, and analyze these parameters in parallel in Gunn rats that are deficient in bilirubin catabolism and develop postnatal hyperbilirubinemia.// Methods: Gunn rats bearing a mutation in UGT1a genes were used. The neurovascular network was analyzed by immunofluorescence stereomicroscopy. The integrity of the barriers was evaluated by [14C]-sucrose permeability measurement. CSF cytokine levels were measured by multiplex immunoassay. The choroid plexus-CSF system response to an inflammatory challenge was assessed by enumerating CSF leukocytes.// Results: In normobilirubinemic animals, the neurovascular network expands postnatally and displays stage-specific regional variations in its complexity. Network expansion is not affected by hyperbilirubinemia. Permeability of the blood–brain and blood–CSF barriers to sucrose decreases between one- and 9-day-old animals, and does not differ between normobilirubinemic and hyperbilirubinemic rats. Cytokine profiles differ between CSF and plasma in all 1-, 9-, and 18-day-old animals. The CSF cytokine profile in 1-day-old animals is markedly different from that established in older animals. Hyperbilirubinemia perturbs these cytokine profiles only to a very limited extent, and reduces CSF immune cell infiltration triggered by systemic exposure to a bacterial lipopeptide.// Conclusion: The data highlight developmental specificities of the blood–brain barrier organization and of CSF cytokine content. They also indicate that a direct effect of bilirubin on the vascular system organization, brain barriers morphological integrity, and inflammatory response of the choroid plexus-CSF system is not involved in the alteration of brain functions induced by severe neonatal jaundice./

Clinical Imaging of Choroid Plexus in Health and in Brain Disorders: A Mini-Review

The choroid plexuses (ChPs) perform indispensable functions for the development, maintenance and functioning of the brain. Although they have gained considerable interest in the last years, their involvement in brain disorders is still largely unknown, notably because their deep location inside the brain hampers non-invasive investigations. Imaging tools have become instrumental to the diagnosis and pathophysiological study of neurological and neuropsychiatric diseases. This review summarizes the knowledge that has been gathered from the clinical imaging of ChPs in health and brain disorders not related to ChP pathologies. Results are discussed in the light of pre-clinical imaging studies. As seen in this review, to date, most clinical imaging studies of ChPs have used disease-free human subjects to demonstrate the value of different imaging biomarkers (ChP size, perfusion/permeability, glucose metabolism, inflammation), sometimes combined with the study of normal aging. Although very few studies have actually tested the value of ChP imaging biomarkers in patients with brain disorders, these pioneer studies identified ChP changes that are promising data for a better understanding and follow-up of diseases such as schizophrenia, epilepsy and Alzheimer’s disease. Imaging of immune cell trafficking at the ChPs has remained limited to pre-clinical studies so far but has the potential to be translated in patients for example using MRI coupled with the injection of iron oxide nanoparticles. Future investigations should aim at confirming and extending these findings and at developing translational molecular imaging tools for bridging the gap between basic molecular and cellular neuroscience and clinical research

Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by Bilirubin at the Blood-CSF and Blood-Brain Barriers in the Gunn Rat

Accumulation of unconjugated bilirubin (UCB) in the brain causes bilirubin encephalopathy. Pgp (ABCb1) and Mrp1 (ABCc1), highly expressed in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) respectively, may modulate the accumulation of UCB in brain. We examined the effect of prolonged exposure to elevated concentrations of UCB on expression of the two transporters in homozygous, jaundiced (jj) Gunn rats compared to heterozygous, not jaundiced (Jj) littermates at different developmental stages (2, 9, 17 and 60 days after birth). BBB Pgp protein expression was low in both jj and Jj pups at 9 days (about 16–27% of adult values), despite the up-regulation in jj animals (2 and 1.3 fold higher than age matched Jj animals at P9 and P17–P60, respectively); Mrp1 protein expression was barely detectable. Conversely, at the BCSFB Mrp1 protein expression was rather high (60–70% of the adult values) in both jj and Jj at P2, but was markedly (50%) down-regulated in jj pups starting at P9, particularly in the 4th ventricle choroid plexuses: Pgp was almost undetectable. The Mrp1 protein down regulation was accompanied by a modest up-regulation of mRNA, suggesting a translational rather than a transcriptional inhibition. In vitro exposure of choroid plexus epithelial cells obtained from normal rats to UCB, also resulted in a down-regulation of Mrp1 protein. These data suggest that down-regulation of Mrp1 protein at the BSCFB, resulting from a direct effect of UCB on epithelial cells, may impact the Mrp1-mediated neuroprotective functions of the blood-cerebrospinal fluid barrier and actually potentiate UCB neurotoxicity

Implication des interfaces sang-cerveau dans l'élimination de la prostaglandine E2 hors du système nerveux central

PARIS-BIUP (751062107) / SudocSudocFranceF

Cerebral concentration and toxicity of endocrine disrupting chemicals: The implication of blood-brain interfaces

International audienceEndocrine disrupting chemicals (EDCs) act on peripheral endocrine organs or interfere with general endocrine pathways. Several EDCs alter the central regulation of neuroendocrine pathways, and affect neurological functions, and as such can be classified as neurotoxic molecules. Environmental pollutants classified as EDCs and affecting the central nervous system include perfluoroalcanes, parabens, phthalates, organotins, bisphenols, benzophenones, polychlorinated biphenyls, and dioxins. In this review we provide a brief description of these families of EDCs. We report and compare the EDC concentrations measured in the brain of humans and wild animals naturally exposed to these molecules, as well as in the brain of laboratory animals experimentally exposed to EDCs. The importance of using sophisticated analytical tools to detect EDCs in the brain is pointed out. The ability of blood-brain interfaces to reduce the brain exposition to EDCs in adult and during development is discussed in relation with the specific morphological, transport and metabolic properties of these cellular layers. Finally, we review the evidence that blood-brain interfaces neuroprotective functions can be altered by EDCs, a process that may participate to the central toxic action of these molecules. Overall this analysis points to the implication of blood-brain interfaces in setting the extent of central EDCs toxicity, although most evidences are indirect. Therefore, more specific blood-brain interface-oriented studies are called for in this field of EDC neurotoxicology

La barrière sang-liquide céphalo-rachidien dans un environnement proinflammatoire (perturbations fonctionnelles de l'épithélium des plexus choroïdes exposé à des lymphocytes T activés par une infection rétrovirale)

L'interface entre le sang et le liquide céphalo-rachidien (LCR) est localisée au niveau de l'épithélium des plexus choroïdes (PC). L'existence de jonctions serrées et de transporteurs spécifiques lui confère des fonctions de protection du cerveau. En utilisant un modèle d'étude des interactions entre l'épithélium choroïdien et des lymphocytes T activés par le rétrovirus HTLV-1, nous montrons que des facteurs sécrétés par les cellules immunes infectées induisent une perturbation des fonctions de la barrière sang-LCR, notamment une diminution de l'efflux d'anions organiques tels la prostaglandine pro-inflammatoire PGE2. L'analyse des mécanismes impliqués indique un rôle clé du TNF- et de l'IL-1. Sous l'action de ces cytokines, une augmentation de la sécrétion par les PC de métalloprotéinases matricielles (MMP), molécules associées aux processus neuro-inflammatoires, est également observée. La diminution de l'élimination de PGE2 hors du LCR ainsi que l'augmentation de la sécrétion de MMP par les PC, impliquent la barrière sang-LCR dans les processus physiopathologiques liés à une inflammation ou une infectionLYON1-BU.Sciences (692662101) / SudocSudocFranceF