Blood Brain Barrier Group

Baton Rouge, LA, United States

Blood Brain Barrier Group

Baton Rouge, LA, United States

Time filter

Source Type

Tu H.,Blood Brain Barrier Group | Tu H.,Shanghai JiaoTong University | Hsuchou H.,Blood Brain Barrier Group | Kastin A.J.,Blood Brain Barrier Group | And 2 more authors.
FASEB Journal | Year: 2010

Impairment in blood-to-brain transport of leptin is a major cause as well as consequence of obesity. Leptin crosses the blood-brain barrier by transcytosis rather than undergoing intracellular degradation. Results from previous studies have indicated that the membrane juxtapositional cytoplasmic sequence of the leptin receptor ObR is responsible for leptin transport. To identify the specific structural domains, we generated a series of ObR truncates with different lengths of the intracellular sequence, overexpressed them in 3 types of mammalian cells including cerebral endothelia, and quantified leptin binding and endocytosis. All mutant ObRs were able to bind and mediate the internalization of leptin. Surprisingly, ObR860, a construct with no cytoplasmic sequence, could act like the classical ObRa transporter in internalizing leptin. There were some cell type-dependent variations in the intracellular trafficking of Alexa-labeled leptin when mediated by ObR860 or ObRa because of differential involvement of membrane microdomains, as shown by use of the clathrin inhibitor chlorpromazine and the dynamin inhibitor Dynasore. The clathrin- and dynamin-mediated endocytosis of leptin contrasts with the lack of effect of the caveolae inhibitors nystatin and filipin. Thus, leptin-induced internalization of the ligand-receptor complex can occur without specific sorting signals in the cytoplasmic region of ObR. This novel finding may have significant implications for leptin transport. © FASEB.

Jayaram B.,Wayne State University | Jayaram B.,Blood Brain Barrier Group | Kowluru A.,Wayne State University
Cellular Physiology and Biochemistry | Year: 2012

Background: Recent fndings from our laboratory have demonstrated that glucose-stimulated insulin secretion (GSIS) involves interplay between a variety of small G proteins belonging to the Rho (e.g., Cdc42 and Rac1) and ADP-ribosylation factor (e.g., Arf6) subfamilies. Using immunological, pharmacological and molecular biological approaches, we have also identifed guanine nucleotide exchange factors (GEFs) for Rac1 (e.g., Tiam1) and Arf6 (e.g., ARNO) in clonal INS-1 832/13 cells, normal rat islets and human islets. As a logical extension to these studies, we investigated, herein, potential downstream signaling steps involved in Arf6/ARNO-mediated GSIS. Methods: Using a selective pharmacological inhibitor of ARNO/Arf6 signaling axis (e.g., secinH3) we assessed regulatory roles for Arf6/ARNO in promoting phospholipase D (PLD), phagocytic NADPH oxidase (Nox2), reactive oxygen species (ROS), extracellularregulated kinases (ERK 1/2) and coflin (actin-severing protein] signaling steps in clonal INS-1 832/13 cells. Results: Our data suggested a marked inhibition by secinH3 of glucose-induced PLD activation, ERK1/2 phosphorylation and dephosphorylation of coflin, suggesting that Arf6/ARNO signaling mediates PLD, ERK1/2 and coflin activation in beta-cells. In addition, secinH3 blocked glucose-induced Nox2 activation and associated ROS generation, thus placing Nox downstream to Arf6/ARNO signaling step. Lastly, we also demonstrate a signifcantly higher coflin phosphorylation (inactive) in islets derived from type 2 diabetic human donors as well as the Zucker Diabetic Fatty (ZDF) rat, a model for type 2 diabetes. Conclusion: Together, our current fndings identify signaling steps downstream to ARNO/Arf6 axis leading to insulin secretion. Copyright © 2012 S. Karger AG, Basel.

Pan W.,Blood Brain Barrier Group | Pan W.,Biopotentials L.L.C. | Kastin A.J.,Blood Brain Barrier Group
Neuroscience and Biobehavioral Reviews | Year: 2014

Both obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are increasing health concerns. The objective of this study is to review systematically the effects of OSA on the development of AD. The search was conducted in PubMed and Cochrane CENTRAL, and followed by a manual search of references of published studies. Cross-sectional, cohorts, and randomized clinical trials were reviewed. Besides clinical studies, we also discuss neuroimaging data, experimental animal evidence, and molecular mechanisms. Although a causal relationship between OSA and AD is not yet established, OSA induces neurodegenerative changes as a result of two major contributing processes: sleep fragmentation and intermittent hypoxia. As such, inflammation and cellular stress are sufficient to impair cell-cell interactions, synaptic function, and neural circuitry, leading to a decline of cognitive behavior. Sustained OSA could promote cognitive dysfunction, overlapping with that in AD and other neurodegenerative diseases. Early treatment by positive airway pressure and other current standards of care should have a positive impact to alleviate structural and functional deterioration. With better understanding of the cellular and neurophysiological mechanisms by which OSA contributes to AD, we may identify novel molecular targets for intervention. © 2014 Elsevier Ltd.

He J.,Blood Brain Barrier Group | Kastin A.J.,Blood Brain Barrier Group | Wang Y.,Blood Brain Barrier Group | Pan W.,Blood Brain Barrier Group
Journal of Molecular Neuroscience | Year: 2014

Chronic sleep fragmentation (SF), common in patients with sleep apnea, correlates with the development of obesity. We hypothesized that SF differentially affects neurobehavior in lean wild-type (WT) and obese pan-leptin receptor knockout (POKO) mice fed the same normal diet. First, we established an SF paradigm by interrupting sleep every 2 min during the inactive light span. The maneuver was effective in decreasing sleep duration and bout length, and in increasing sleep state transition and waking, without significant rebound sleep in the dark span. Changes of sleep architecture were evident in the light span and consistent across days 1–10 of SF. There was reduced NREM, shortened sleep latency, and increased state transitions. During the light span of the first day of SF, there also was reduction of REM and increased delta power of slow-wave sleep. Potential effects of SF on thermal pain threshold, locomotor activity, and anxiety were then tested. POKO mice had a lower circadian amplitude of pain latency than WT mice in the hot plate test, and both groups had lowest tolerance at 4 pm (zeitgeber time (ZT) 10) and longest latency at 4 am (ZT 22). SF increased the pain threshold in WT but not in POKO mice when tested at 8 a.m. (ZT 2). Both the POKO mutation and SF resulted in reduced physical activity and increased anxiety, but there was no additive effect of these two factors. Overall, SF and the POKO mutation differentially regulate mouse behavior. The results suggest that obesity can blunt neurobehavioral responses to SF. © 2014, Springer Science+Business Media New York.

Wu X.,Blood Brain Barrier Group | Pan W.,Blood Brain Barrier Group | He Y.,Blood Brain Barrier Group | Hsuchou H.,Blood Brain Barrier Group | Kastin A.J.,Blood Brain Barrier Group
Journal of Neuroimmunology | Year: 2010

Interleukin (IL)-15 can cross the blood-brain barrier to act on its specific brain receptor (IL15Rα) and co-receptors. The important roles of neuronal IL15 and IL15Rα in experimental autoimmune encephalomeylitis (EAE) are suggested by the upregulation of IL15Rα mRNA in different regions of the brain and spinal cord, and by double-labeling immunohistochemistry showing neuronal localization of IL15 and IL15Rα in different neurons. Contrary to expectations, IL15 treatment lessened EAE severity. IL15 knockout mice showed heightened susceptibility to EAE with significantly higher scores that were decreased by treatment with IL15. Thus, IL15 improves this CNS autoimmune disorder as a potential therapeutic agent. © 2010 Elsevier B.V.

Ouyang S.,Blood Brain Barrier Group | Hsuchou H.,Blood Brain Barrier Group | Kastin A.J.,Blood Brain Barrier Group | Wang Y.,Blood Brain Barrier Group | And 2 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2014

The blood-brain barrier (BBB) is a regulatory interface between the central nervous system and the rest of the body. However, BBB changes in obesity and metabolic syndrome have not been fully elucidated. We hypothesized that obesity reduces energy metabolism in the cerebral microvessels composing the BBB, reflected by downregulation of protein expression and function. We performed comparative proteomic analyses in enriched microvessels from the cerebral cortex of mice 2 months after ingestion of a high-fat diet or regular rodent chow. In mice with diet-induced obesity (DIO), there was downregulation of 47 proteins in the cerebral microvessels, including cytoskeletal proteins, chaperons, enzymes, transport-related proteins, and regulators for transcriptional and translational activities. Only two proteins, involved in messenger RNA (mRNA) transport and processing, were upregulated. The changes of these proteins were further validated by quantitative polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining of freshly isolated microvessels, in samples obtained from different batches of mice. The predominant downregulation suggests that DIO suppresses metabolic activity of BBB microvessels. The finding of a hypometabolic state of the BBB in mice at the chronic stage of DIO is unexpected and unprecedented; it may provide novel mechanistic insight into how obesity influences CNS function via regulatory changes of the BBB. © 2014 ISCBFM. All rights reserved.

Pan W.,Blood Brain Barrier Group | Stone K.P.,Blood Brain Barrier Group | Hsuchou H.,Texas Tech University Health Sciences Center | Manda V.K.,Blood Brain Barrier Group | And 2 more authors.
Current Pharmaceutical Design | Year: 2011

The blood-brain barrier (BBB) provides a vast interface for cytokines to affect CNS function. The BBB is a target for therapeutic intervention. It is essential, therefore, to understand how cytokines interact with each other at the level of the BBB and how secondary signals modulate CNS functions beyond the BBB. The interactions between cytokines and lipids, however, have not been fully addressed at the level of the BBB. Here, we summarize current understanding of the localization of cytokine receptors and transporters in specific membrane microdomains, particularly lipid rafts, on the luminal (apical) surface of the microvascular endothelial cells composing the BBB. We then illustrate the clinical context of cytokine effects on the BBB by neuroendocrine regulation and amplification of inflammatory signals. Two unusual aspects discussed are signaling crosstalk by different classes of cytokines and genetic regulation of drug efflux transporters. We also introduce a novel area of focus on how cytokines may act through nuclear hormone receptors to modulate efflux transporters and other targets. A specific example discussed is the ATP-binding cassette transporter-1 (ABCA-1) that regulates lipid metabolism. Overall, cytokine signaling at the level of the BBB is a crucial feature of the dynamic regulation that can rapidly change BBB function and affect brain health and disease. © 2011 Bentham Science Publishers.

Hsuchou H.,Blood Brain Barrier Group | Kastin A.J.,Blood Brain Barrier Group | Mishra P.K.,Blood Brain Barrier Group | Pan W.,Blood Brain Barrier Group
Cellular Physiology and Biochemistry | Year: 2012

Background/Aims: Acute phase C-reactive protein (CRP), elevated in obesity and infammation, is a major binding protein for leptin. It is thought that CRP contributes to leptin resistance by preventing leptin from crossing the blood-brain barrier (BBB). Here we determined how CRP interacts with the BBB and whether it deters leptin from reaching CNS targets. Methods: BBB permeability, compartmental distribution, tracer stability, and expression of tight junction protein and infammatory marker were determined. Results: CRP was stable in blood, but did not permeate the BBB in trace amounts. However, it increased paracellular permeability at a higher dose. Agouti viable (Avy) mice with adult-onset obesity show higher CRP entry into the brain. CRP did not permeate hCMEC/D3 cells nor change zona occludin-1 or cyclooxygenase-2 expression. An intermediate dose of CRP had no effect on leptin transport across the BBB after co-treatment. Thus, acute interactions between CRP and leptin at the BBB level were negligible and did not explain the leptin resistance seen in obesity. Conclusions: The interactions of CRP and the BBB are a two-phase process, with increased paracellular permeability at a high dose that enables its entry into the CNS and serves to induce reactive gliosis and impair CNS function. Copyright © 2012 S. Karger AG, Basel.

He J.,Blood Brain Barrier Group | Hsuchou H.,Blood Brain Barrier Group | He Y.,Blood Brain Barrier Group | Kastin A.J.,Blood Brain Barrier Group | And 2 more authors.
Journal of Neuroscience | Year: 2014

The blood- brain barrier (BBB) is a large regulatory and exchange interface between the brain and peripheral circulation. We propose that changes of the BBB contribute to many pathophysiological processes in the brain of subjects with chronic sleep restriction (CSR). To achieve CSR that mimics a common pattern of human sleep loss, we quantified a new procedure of sleep disruption in mice by a week of consecutive sleep recording. We then tested the hypothesis that CSR compromises microvascular function. CSR not only diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of the BBB, but it also decreased 2-deoxy-glucose uptake by the brain. The expression of several tight junction proteins also was decreased, whereas the level of cyclooxygenase-2 increased. This coincided with an increase of paracellular permeability of the BBB to the small tracers sodium fluorescein and biotin. CSR for 6 d was sufficient to impair BBB structure and function, although the increase of paracellular permeability returned to baseline after 24 h of recovery sleep. This merits attention not only in neuroscience research but also in public health policy and clinical practice. © 2014 the authors.

Stone K.P.,Blood Brain Barrier Group | Kastin A.J.,Blood Brain Barrier Group | Pan W.,Blood Brain Barrier Group
Cellular Physiology and Biochemistry | Year: 2011

Interleukin (IL)-15 and its receptors are induced by tumor necrosis factor α (TNF) in the cerebral endothelial cells composing the blood-brain barrier, but it is not yet clear how IL-15 modulates endothelial function. Contrary to the known induction of JAK/STAT3 signaling, here we found that nuclear factor (NF)-κB is mainly responsible for IL-15 actions on primary brain microvessel endothelial cells and cerebral endothelial cell lines. IL-15-induced transactivation of an NFκB luciferase reporter resulted in phosphorylation and degradation of the inhibitory subunit IκB that was followed by phosphorylation and nuclear translocation of the p65 subunit of NFκB. An IκB kinase inhibitor Bay 11-7082 only partially inhibited IL-15-induced NFκB luciferase activity. The effect of IL-15 was mediated by its specific receptor IL-15Rα, since endothelia from IL-15Rα knockout mice showed delayed nuclear translocation of p65, whereas those from knockout mice lacking a co-receptor IL-2Rγ did not show such changes. At the mRNA level, IL-15 and TNF showed similar effects in decreasing the tight junction protein claudin-2 and increasing the p65 subunit of NFκB but exerted different regulation on caveolin-1 and vimentin. Taken together, NFκB is a major signal transducer by which IL-15 affects cellular permeability, endocytosis, and intracellular trafficking at the level of the blood-brain barrier. © 2011 S. Karger AG, Basel.

Loading Blood Brain Barrier Group collaborators
Loading Blood Brain Barrier Group collaborators