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- Liddelow, S. A., et al.
(författare)
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Mechanisms That Determine the Internal Environment of the Developing Brain: A Transcriptomic, Functional and Ultrastructural Approach
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- We provide comprehensive identification of embryonic (E15) and adult rat lateral ventricular choroid plexus transcriptome, with focus on junction-associated proteins, ionic influx transporters and channels. Additionally, these data are related to new structural and previously published permeability studies. Results reveal that most genes associated with intercellular junctions are expressed at similar levels at both ages. In total, 32 molecules known to be associated with brain barrier interfaces were identified. Nine claudins showed unaltered expression, while two claudins (6 and 8) were expressed at higher levels in the embryo. Expression levels for most cytoplasmic/regulatory adaptors (10 of 12) were similar at the two ages. A few junctional genes displayed lower expression in embryos, including 5 claudins, occludin and one junctional adhesion molecule. Three gap junction genes were enriched in the embryo. The functional effectiveness of these junctions was assessed using blood-delivered water-soluble tracers at both the light and electron microscopic level: embryo and adult junctions halted movement of both 286Da and 3kDa molecules into the cerebrospinal fluid (CSF). The molecular identities of many ion channel and transporter genes previously reported as important for CSF formation and secretion in the adult were demonstrated in the embryonic choroid plexus (and validated with immunohistochemistry of protein products), but with some major age-related differences in expression. In addition, a large number of previously unidentified ion channel and transporter genes were identified for the first time in plexus epithelium. These results, in addition to data obtained from electron microscopical and physiological permeability experiments in immature brains, indicate that exchange between blood and CSF is mainly transcellular, as well-formed tight junctions restrict movement of small water-soluble molecules from early in development. These data strongly indicate the brain develops within a well-protected internal environment and the exchange between the blood, brain and CSF is transcellular and not through incomplete barriers.
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| 2. |
- Moretti, R., et al.
(författare)
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Melatonin reduces excitotoxic blood-brain barrier breakdown in neonatal rats
- 2015
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522. ; 311, s. 382-397
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Tidskriftsartikel (refereegranskat)abstract
- The blood-brain barrier (BBB) is a complex structure that protects the central nervous system from peripheral insults. Understanding the molecular basis of BBB function and dysfunction holds significant potential for future strategies to prevent and treat neurological damage. The aim of our study was (1) to investigate BBB alterations following excitotoxicity and (2) to test the protective properties of melatonin.Ibotenate, a glutamate analog, was injected intracerebrally in postnatal day 5 (P5) rat pups to mimic excitotoxic injury. Animals were than randomly divided into two groups, one receiving intraperitoneal (i.p.) melatonin injections (5. mg/kg), and the other phosphate buffer saline (PBS) injections. Pups were sacrificed 2, 4 and 18. h after ibotenate injection. We determined lesion size at 5. days by histology, the location and organization of tight junction (TJ) proteins by immunohistochemical studies, and BBB leakage by dextran extravasation. Expression levels of BBB genes (TJs, efflux transporters and detoxification enzymes) were determined in the cortex and choroid plexus by quantitative PCR.Dextran extravasation was seen 2. h after the insult, suggesting a rapid BBB breakdown that was resolved by 4. h. Extravasation was significantly reduced in melatonin-treated pups. Gene expression and immunohistochemical assays showed dynamic BBB modifications during the first 4. h, partially prevented by melatonin. Lesion-size measurements confirmed white matter neuroprotection by melatonin.Our study is the first to evaluate BBB structure and function at a very early time point following excitotoxicity in neonates. Melatonin neuroprotects by preventing TJ modifications and BBB disruption at this early phase, before its previously demonstrated anti-inflammatory, antioxidant and axonal regrowth-promoting effects. © 2015 IBRO.
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| 3. |
- Mottahedin, Amin, et al.
(författare)
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N-acetylcysteine inhibits bacterial lipopeptide-mediated neutrophil transmigration through the choroid plexus in the developing brain
- 2020
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The etiology of neurological impairments associated with prematurity and other perinatal complications often involves an infectious or pro-inflammatory component. The use of antioxidant molecules have proved useful to protect the neonatal brain from injury. The choroid plexuses-CSF system shapes the central nervous system response to inflammation at the adult stage, but little is known on the neuroimmune interactions that take place at the choroidal blood-CSF barrier during development. We previously described that peripheral administration to neonatal mice of the TLR2 ligand PAM3CSK4 (P3C), a prototypic Gram-positive bacterial lipopeptide, induces the migration of innate immune cells to the CSF. Here we showed in neonatal rats exposed to P3C that the migration of neutrophils into the CSF, which occurred through the choroid plexuses, is abolished following administration of the antioxidant drug N-acetylcysteine. Combining light sheet microscopy imaging of choroid plexus, a differentiated model of the blood-CSF barrier, and multiplex cytokine assays, we showed that the choroidal epithelium responds to the bacterial insult by a specific pattern of cytokine secretion, leading to a selective accumulation of neutrophils in the choroid plexus and to their trafficking into CSF. N-acetylcysteine acted by blocking neutrophil migration across both the endothelium of choroidal stromal vessels and the epithelium forming the blood-CSF barrier, without interfering with neutrophil blood count, neutrophil tropism for choroid plexus, and choroidal chemokine-driven chemotaxis. N-acetylcysteine reduced the injury induced by hypoxia-ischemia in P3C-sensitized neonatal rats. Overall, the data show that a double endothelial and epithelial check point controls the transchoroidal migration of neutrophils into the developing brain. They also point to the efficacy of N-acetylcysteine in reducing the deleterious effects of inflammation-associated perinatal injuries by a previously undescribed mechanism, i.e. the inhibition of innate immune cell migration across the choroid plexuses, without interfering with the systemic inflammatory response to infection.
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