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Post by Max on Jul 4, 2005 5:43:57 GMT -5
The blood-brain barrier (BBB) is a metabolic and physiological barrier important for maintaining brain homeostasis [5]. Integrity of the blood-brain barrier is essential for the normal functioning of CNS [6].
Inhibition of insulin transport to the brain, inhibition of transcytosis and altered permeability of the blood brain barrier
The Hoffman la Roche corporation itself, salesagent of (Ro)accutane, has admitted to the finding of an increased alkaline phosphatase in acne-subjects exposed to the toxin [0]. A positive correlation between ecto-ALP activity and (125)I-insulin incorporation (r = 0.82; P < 0.0001) was shown in cultured rat brain endothelial cells, suggesting that insulin entry into the blood-brain barrier may be modulated through ALP [1]. Cellular retinol binding protein (CRBP) was demonstrated in cells that form the blood brain barrier in humans and rats, specifically within endothelial cells of the brain microvasculature and in cuboidal epithelial cells of the choroid plexus. Translocation of retinol across the blood brain barrier is suggested to occur via RBP uptake from the plasma with subsequent transcellular movement of retinol as a complex with CRBP [6]. A disturbance in the continous translocation of retinol to the brain following a (Ro)accutane exposure is highly likely. Significant effects of hypervitaminosis A on the choroid plexus in humans was discovered allready in the 1960s [7]. Plasma transthyretin (TTR, formerly called prealbumin) is a 55-kd protein that participates in the plasma transport of both thyroxine and retinol (vitamin A). TTR concentrations are disproportionately high in human ventricular CSF, suggesting that TTR is either selectively transported across or synthesized de novo within the blood-CSF barrier [8].
The epithelial cells of the choroid plexus are also known to contain specific transport systems for thiamine, ascorbic acid, pyridoxine, folate and inositol [6].
Protein kinase C (PKC) isoforms have been found to modulate permeability of the blood brain barrier [5].
Inhibition of glucose transport to the brain, worsening symptoms with age in (Ro)accutane exposed subjects
Glucose transporter 1 (GLUT1) is the primary glucose transporter in the blood brain barrier [2]. In rats, it is concluded that alterations in cerebral GLUT-1 content in response to altered thyroid state are age-specific [3]. In human acne-subjects exposed to (Ro)accutane, levels of thyroxine and triiodothyronine were significantly lower after exposure (p less than 0.05), indicating a (Ro)accutane induced clinical thyroid deficiency (hypothyroidism) [4].
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Post by Max on Jul 4, 2005 5:44:21 GMT -5
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Post by Max on Jul 4, 2005 5:44:41 GMT -5
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Post by Max on Jul 4, 2005 5:45:46 GMT -5
References:
[1] Calhau C, Martel F, Pinheiro-Silva S, Pinheiro H, Soares-da-Silva P, Hipolito-Reis C, Azevedo I. Modulation of insulin transport in rat brain microvessel endothelial cells by an ecto-phosphatase activity. (2002) J Cell Biochem. 84(2):389-400.
[2] Guo X, Geng M, Du G.
Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood-brain barrier. (2005) Biochem Genet. Apr;43(3-4):175-87.
[3] Mooradian AD, Girgis W, Shah GN.
Thyroid hormone-induced GLUT-1 expression in rat cerebral tissue: effect of age.
(1997) Brain Res. Jan 30;747(1):144-6.
[5] Fleegal MA, Hom S, Borg LK, Davis TP.
Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and post-hypoxic reoxygenation. (2005) Am J Physiol Heart Circ Physiol. Jul 1
[6] MacDonald PN, Bok D, Ong DE. Localization of cellular retinol-binding protein and retinol-binding protein in cells comprising the blood-brain barrier of rat and human. (1990) Proc Natl Acad Sci U S A. Jun;87(11):4265-9.
[7] BECKER NH, SUTTON CH. PATHOLOGIC FEATURES OF THE CHOROID PLEXUS. 1. CYTOCHEMICAL EFFECTS OF HYPERVITAMINOSIS A. (1963) Am J Pathol. Dec;43:1017-30.
[8] Herbert J, Wilcox JN, Pham KT, Fremeau RT Jr, Zeviani M, Dwork A, Soprano DR, Makover A, Goodman DS, Zimmerman EA, et al. Transthyretin: a choroid plexus-specific transport protein in human brain. The 1986 S. Weir Mitchell award. (1986) 1: Neurology. Jul;36(7):900-11.
J Cell Sci. 2004 Oct 1;117(Pt 21):5071-8. Epub 2004 Sep 21. Related Articles, Links
Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier.
Pan W, Kastin AJ, Zankel TC, van Kerkhof P, Terasaki T, Bu G.
Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge 70808, USA. weihong.pan@pbrc.edu
We have sought to identify a high-capacity transport system that mediates transcytosis of proteins from the blood to the brain. The 39 kDa receptor-associated protein (RAP) functions as a specialized endoplasmic reticulum chaperone assisting in the folding and trafficking of members of the low-density lipoprotein (LDL) receptor family. RAP efficiently binds to these receptors and antagonizes binding of other ligands. Previous studies have shown that two large members of the LDL receptor family, LDL receptor-related protein 1 (LRP1) and LDL receptor-related protein 2 (LRP2 or megalin), possess the ability to mediate transcytosis of ligands across the brain capillary endothelium. Here, we tested whether blood-borne RAP crosses the blood-brain barrier (BBB) by LRP1- or megalin-mediated transport by studying the pharmacokinetics of [125I]-RAP transport into the brain in intact mice and across cell monolayers in vitro. Our results show that [125I]-RAP is relatively stable in blood for 30 minutes and has a mean influx constant of 0.62+/-0.08 microl/g-minute from blood to brain. In situ brain perfusion in blood-free buffer shows that transport of [125I]-RAP across the BBB is a saturable process. Capillary depletion of brain homogenates indicates that 70% of [125I]-RAP is localized in the parenchyma rather than in the vasculature of the brain. Results of transport in stably transfected MDCK cells are consistent with the hypothesis that megalin mediates most of the apical-to-basolateral transport across polarized epithelial cells. The inhibition of [125I]-RAP influx by excess RAP and the involvement of megalin indicate the presence of a saturable transport system at the BBB. The higher permeability of RAP compared with that of melanotransferrin and transferrin show that the LRP receptor is a high capacity transport system. These studies suggest that RAP may provide a novel means of protein-based drug delivery to the brain.
PMID: 15383619 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 4, 2005 13:06:07 GMT -5
J Am Soc Nephrol. 2005 Jun 23; [Epub ahead of print] Related Articles, Links
Intraperitoneal Administration of Recombinant Receptor-Associated Protein Causes Phosphaturia via an Alteration in Subcellular Distribution of the Renal Sodium Phosphate Co-Transporter.
Yamagata M, Ozono K, Hashimoto Y, Miyauchi Y, Kondou H, Michigami T.
*Department of Environmental Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health; and Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, Osaka, Japan.
Megalin is a multifunctional endocytic receptor that is expressed in renal proximal tubules and plays critical roles in the renal uptake of various proteins. It was hypothesized that megalin-dependent endocytosis might play a role in renal phosphate reabsorption. For addressing the short-term effects of altered megalin function, a recombinant protein for the soluble form of 39-kD receptor-associated protein (RAP) was administered intraperitoneally to 7-wk-old mice. Histidine (His)-tagged soluble RAP (amino acids 39 to 356) lacking the amino-terminal signal peptide and the carboxy-terminal endoplasmic reticulum retention signal was prepared by bacterial expression (designated His-sRAP). After the direct interaction between His-sRAP and megalin was confirmed, mice were given a single intraperitoneal administration of His-sRAP (3.5 mg/dose). Immunostaining and Western blot analyses demonstrated the uptake of His-sRAP and the accelerated internalization of megalin in proximal tubular cells 1 h after administration. In addition, internalization of the type II sodium/phosphate co-transporter (NaPi-II) was observed. The effects of three sequential administrations of His-sRAP (3.5 mg/dose, three doses at 4-h intervals) then were examined, and increased urinary excretion of low molecular weight proteins, including vitamin D-binding protein, was found, which is consistent with findings reported for megalin-deficient mice. It is interesting that urinary excretion of phosphate was also increased, and the protein level of NaPi-II in the brush border membrane was decreased. Serum concentration of 25-hydroxyvitamin D was decreased, whereas the plasma level of intact parathyroid hormone was not altered by the administration of His-sRAP. The results suggest that the His-sRAP-induced acceleration of megalin-mediated endocytosis caused phosphaturia via altered subcellular distribution of NaPi-II.
PMID: 15976002 [PubMed - as supplied by publisher]
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Post by Max on Jul 15, 2005 7:21:49 GMT -5
Am J Physiol Heart Circ Physiol. 2005 Jul 1; [Epub ahead of print] Related Articles, Links
Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and post-hypoxic reoxygenation.
Fleegal MA, Hom S, Borg LK, Davis TP.
Medical Pharmacology, University of Arizona, Tucson, AZ, USA.
The blood-brain barrier (BBB) is a metabolic and physiological barrier important for maintaining brain homeostasis. The aim of these studies was to determine the role of protein kinase C (PKC) activation in BBB paracellular permeability changes induced by hypoxia and post-hypoxic reoxygenation using in vitro and in vivo BBB models. In rat brain microvessel endothelial cells (RMECs) exposed to hypoxia (1% O2; 24 h), a significant increase in total PKC activity was observed, and this was reduced by post-hypoxic reoxygenation (95% room air/ 5% CO2) for 2 h. The expression of PKCbetaII, PKCgamma, PKCeta, PKCmicro and PKClambda also increased following hypoxia (1% O2; 24 h) and these protein levels remained elevated following post-hypoxic reoxygenation (95% room air/ 5% CO2; 2 h). Increases in the expression of PKCepsilon and PKCzeta were also observed following post-hypoxic reoxygenation (95% room air/ 5% CO2; 2 h). Moreover, inhibition of PKC with chelerythrine chloride (10 microM) attenuated the hypoxia-induced increases in (14)C-sucrose permeability. Similar to what was observed in RMECs, total PKC activity was also stimulated in cerebral microvessels isolated from rats exposed to hypoxia (6% O2; 1 h) and post-hypoxic reoxygenation (room air; 10 min). In contrast, hypoxia (6% O2; 1 h) and post-hypoxic reoxygenation (room air; 10 min) significantly increased the expression levels of only PKCgamma and PKCtheta in the in vivo hypoxia model. These data demonstrate that hypoxia-induced BBB paracellular permeability changes occur via a PKC-dependent mechanism, possibly by differentially regulating the protein expression of the eleven PKC isozymes.
PMID: 15994856 [PubMed - as supplied by publisher]
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Post by Max on Jul 15, 2005 7:27:25 GMT -5
J Neurochem. 2005 Jul;94(1):204-14. Related Articles, Links
Inhibition of phosphoinositide 3 kinase-Akt (protein kinase B)-nuclear factor-kappaB pathway by lovastatin limits endothelial-monocyte cell interaction.
Prasad R, Giri S, Nath N, Singh I, Singh AK.
Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
Integrity of the blood-brain barrier is essential for the normal functioning of CNS. Its disruption contributes to the pathobiology of various inflammatory neurodegenerative disorders. We have shown that the HMG-CoA reductase inhibitor (lovastatin) attenuated experimental autoimmune encephalomyelitis (EAE, an inflammatory disease of CNS) in rodents by inhibiting the infiltration of mononuclear cells into the CNS. Here, using an in vitro system, we report that lovastatin inhibits endothelial-monocyte cell interaction by down-regulating the expression of vascular cell adhesion molecule-1 and E-selectin by inhibiting the phosphoinositide 3 kinase (PI3-kinase)/protein kinase B (Akt)/nuclear factor-kappa B (NF-kappaB) pathway in endothelial cells. It inhibits tumor necrosis factor alpha (TNFalpha)-induced PI3-kinase, Akt and NF-kappaB activation in these cells. Co-transfection of constitutively active forms of PI3-kinase and Akt reversed the lovastatin-mediated inhibition of TNFalpha-induced adhesion, as well as activation of NF-kappaB, indicating the involvement of the PI3-kinase/Akt pathway in the interaction of adhesion molecules and the process of adhesion. This study reports that lovastatin down-regulates the pathway affecting the expression and interaction of adhesion molecules on endothelial cells, which in turn restricts the migration and infiltration of mononuclear cells thereby attenuating the pathogenesis of inflammatory diseases.
PMID: 15953363 [PubMed - in process]
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Post by Max on Jul 15, 2005 7:33:13 GMT -5
Biochem Genet. 2005 Apr;43(3-4):175-87. Related Articles, Links
Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood-brain barrier.
Guo X, Geng M, Du G.
Department of Pharmacology, Marine Drug and Food Institute, Ocean University of China, Qingdao 266003, China.
Facilitative glucose transport is mediated by one or more of the members of the closely related glucose transporter (GLUT) family. Thirteen members of the GLUT family have been described thus far. GLUT1 is a widely expressed isoform that provides many cells with their basic glucose requirement. It is also the primary transporter across the blood-brain barrier. This review describes the distribution and expression of GLUT1 in brain in different pathophysiological conditions including Alzheimer's disease, epilepsy, ischemia, or traumatic brain injury. Recent investigations show that GLUT1 mediates the transport of some neuroactive drugs, such as glycosylated neuropeptides, low molecular weight heparin, and D-glucose derivatives, across the blood-brain barrier as a delivery system. By utilizing such highly specific transport mechanisms, it should be possible to establish strategies to regulate the entry of candidate drugs.
PMID: 15932065 [PubMed - in process]
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Post by ddddyyyy on Jul 19, 2009 22:40:44 GMT -5
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