scholarly journals Methamphetamine Disrupts Blood–Brain Barrier Function by Induction of Oxidative Stress in Brain Endothelial Cells

2009 ◽  
Vol 29 (12) ◽  
pp. 1933-1945 ◽  
Author(s):  
Servio H Ramirez ◽  
Raghava Potula ◽  
Shongshan Fan ◽  
Tess Eidem ◽  
Anil Papugani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Endothelial Injury ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Monocyte Migration ◽  
Enhanced Production ◽  
Blood Brain ◽  
Neurotoxic Effects

Methamphetamine (METH), a potent stimulant with strong euphoric properties, has a high abuse liability and long-lasting neurotoxic effects. Recent studies in animal models have indicated that METH can induce impairment of the blood–brain barrier (BBB), thus suggesting that some of the neurotoxic effects resulting from METH abuse could be the outcome of barrier disruption. In this study, we provide evidence that METH alters BBB function through direct effects on endothelial cells and explore possible underlying mechanisms leading to endothelial injury. We report that METH increases BBB permeability in vivo, and exposure of primary human brain microvascular endothelial cells (BMVEC) to METH diminishes the tightness of BMVEC monolayers in a dose- and time-dependent manner by decreasing the expression of cell membrane-associated tight junction (TJ) proteins. These changes were accompanied by the enhanced production of reactive oxygen species, increased monocyte migration across METH-treated endothelial monolayers, and activation of myosin light chain kinase (MLCK) in BMVEC. Antioxidant treatment attenuated or completely reversed all tested aspects of METH-induced BBB dysfunction. Our data suggest that BBB injury is caused by METH-mediated oxidative stress, which activates MLCK and negatively affects the TJ complex. These observations provide a basis for antioxidant protection against brain endothelial injury caused by METH exposure.

Abstract 218: Pericytic Laminin Regulates Blood-Brain Barrier Integrity in an Age-Dependent Manner

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Yao Yao ◽  
Jyoti Gautam ◽  
Xuanming Zhang
Keyword(s):  
Endothelial Cells ◽  
Basement Membrane ◽  
Blood Brain Barrier ◽  
Vessel Density ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Vascular Integrity ◽  
Blood Brain ◽  
Age Dependent

Introduction: Laminin, a major component of the basement membrane, plays an important role in blood brain barrier (BBB) regulation. At the neurovascular unit, astrocytes, brain endothelial cells, and pericytes synthesize and deposit different laminin isoforms into the basement membrane. Previous studies from our laboratory showed that loss of astrocytic laminin induces age-dependent and region-specific BBB breakdown and intracerebral hemorrhage, suggesting a critical role of astrocytic laminin in vascular integrity maintenance. Laminin α4 (predominantly generated by endothelial cells) has been shown to regulate vascular integrity at embryonic/neonatal stage. The role of pericytic laminin in vascular integrity, however, remains elusive. Methods: We investigated the function of pericyte-derived laminin in vascular integrity using laminin conditional knockout mice. Specifically, laminin floxed mice were crossed with PDGFRβ-Cre line to generate mutants (PKO) with laminin deficiency in PDGFRβ + cells, which include both pericytes and vascular smooth muscle cells (vSMCs). To distinguish the contribution of pericyte- and vSMC-derived laminin, we also generated a vSMC-specific condition knockout line (TKO) by crossing the laminin floxed mice with Transgelin-Cre mice. In this study, mice of both genders on a C57Bl6 background were used. At least 5-6 animals were used in biochemical and histological analyses in this study. Results: Pericyte-derived laminin was abrogated in all PKO mice. However, only old but not young PKO mice showed signs of BBB breakdown and reduced vessel density, suggesting age-dependent changes. Consistent with these data, further mechanistic studies revealed reduced tight junction proteins, diminished AQP4 expression, and deceased pericyte coverage in old but not young PKO mice. In addition, neither BBB disruption nor decreased vessel density was observed in TKO mice, suggesting that these vascular defects are due to loss of pericyte- rather than vSMC-derived laminin. Conclusions: These results strongly suggest that pericyte-derived laminin active regulates BBB integrity and vessel density in an age-dependent manner. I would like this abstract to be considered for the Stroke Basic Science Award.

scholarly journals Plasmodium falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood–brain barrier in cerebral malaria

2021 ◽  
Vol 218 (3) ◽  
Author(s):  
Yvonne Adams ◽  
Rebecca W. Olsen ◽  
Anja Bengtsson ◽  
Nanna Dalgaard ◽  
Mykola Zdioruk ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasmodium Falciparum ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Cell Swelling ◽  
Dependent Manner ◽  
Brain Endothelial Cells ◽  
Blood Brain ◽  
The Brain

Cerebral malaria (CM) is caused by the binding of Plasmodium falciparum–infected erythrocytes (IEs) to the brain microvasculature, leading to inflammation, vessel occlusion, and cerebral swelling. We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)– and endothelial protein C receptor (EPCR)–binding P. falciparum parasites to these symptoms, but the mechanism driving the pathogenesis has not been identified. Here, we used a 3D spheroid model of the blood–brain barrier (BBB) to determine unexpected new features of IEs expressing the dual-receptor binding PfEMP1 parasite proteins. Analysis of multiple parasite lines shows that IEs are taken up by brain endothelial cells in an ICAM-1–dependent manner, resulting in breakdown of the BBB and swelling of the endothelial cells. Via ex vivo analysis of postmortem tissue samples from CM patients, we confirmed the presence of parasites within brain endothelial cells. Importantly, this discovery points to parasite ingress into the brain endothelium as a contributing factor to the pathology of human CM.

scholarly journals SCIDOT-41. NANOTHERAPEUTIC TARGETING OF TUMOR ENDOTHELIUM FOR ENHANCING DRUG DELIVERY PAST THE BLOOD-BRAIN BARRIER

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi280-vi280
Author(s):  
Hiroto Kiguchi ◽  
Mandana Manzari ◽  
Jake Vaynshteyn ◽  
Jeffrey Gerwin ◽  
Daniel Tylawsky ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Low Dose ◽  
Tumor Vasculature ◽  
Adult Brain ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Shh Pathway ◽  
Blood Brain

Abstract OBJECTIVE The Sonic Hedgehog (SHH) medulloblastoma subgroup accounts for ~25% of all cases and has an intermediate prognosis. Current conventional therapies result in devastating morbidities including intellectual disability and secondary malignancies. Although molecularly targeted agents that inhibit the SHH pathway have demonstrated clinical efficacy, recent studies have shown on-target secondary toxicities on bone development suggesting new therapeutic approaches are needed. METHODS We investigated the efficacy of the SHH pathway inhibitor, Vismodegib packaged in a fucoidan-based nanoparticle (Fi-Vis) that targets P-selectin, a protein overexpressed on vascular endothelial cells and induced by low-dose ionizing radiation (XRT) in a time- and dose-dependent manner. This P-selectin targeting nanoparticle drug delivery system shows selectivity toward tumor vasculature and not normal brain vasculature in a genetic SHH medulloblastoma mouse model as assessed by ex vivo infrared imaging and two-photon intravital imaging. RESULTS Quantitative RT-PCR analysis of SHH medulloblastoma tissue following single dose XRT and Fi-Vis treatment (10mg/kg) showed a synergistic inhibition of Gli1 expression (>90% target inhibition). Furthermore, we demonstrate that very low dose XRT (0.25Gy) can induce P-selectin expression specifically within MB tumor vasculature and synergize with low dose Fi-Vis (10mg/kg) to significantly enhance mouse survival (p<0.01) when compared to radiation or Fi-Vis alone. Furthermore, assessment of bone toxicity using micro-CT and histological analysis following Fi-Vis administration in postnatal (P10) mice shows no bone toxicity when compared to free Vismodegib. Finally, in vitro studies using mouse brain endothelial cells suggest at least in part a caveolin-1 mediated transcytosis mechanism of crossing the endothelial blood-brain barrier. CONCLUSIONS These data suggest applicability of combined XRT and tumor vasculature-targeted nanotherapeutic dose de-escalation strategies for SHH medulloblastoma with implications for other pediatric and adult brain tumors.

scholarly journals DDEL-15. NANOTHERAPEUTIC TARGETING OF TUMOR ENDOTHELIUM FOR ENHANCING DRUG DELIVERY PAST THE BLOOD-BRAIN BARRIER

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii286-iii286
Author(s):  
Hiro Kiguchi ◽  
Daniel Tylawsky ◽  
Jake Vaynshteyn ◽  
Jeffrey Gerwin ◽  
Mandana Manzari ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Low Dose ◽  
Brain Barrier ◽  
Pcr Analysis ◽  
Normal Brain ◽  
Dependent Manner ◽  
Shh Pathway ◽  
Blood Brain ◽  
Tumor Endothelium

Abstract OBJECTIVE The Sonic Hedgehog (SHH) medulloblastoma subgroup accounts for ~25% of all cases and has an intermediate prognosis. Current therapies result in devastating morbidities including intellectual disability and secondary malignancies. Although molecularly targeted agents against the SHH pathway have demonstrated efficacy, on-target bone toxicities suggest new therapeutic approaches are needed. METHODS We investigated the SHH pathway inhibitor, vismodegib, packaged in a fucoidan-based nanoparticle (Fi-Vis) that targets P-selectin expressed on endothelial cells and induced by low-dose ionizing radiation (XRT) in a time- and dose-dependent manner. This P-selectin targeting nanoparticle shows selectivity toward tumor and not normal brain vasculature in a GEM SHH medulloblastoma model as assessed by ex vivo infrared imaging and molecular studies. RESULTS Quantitative RT-PCR analysis of SHH medulloblastoma following single dose XRT and Fi-Vis treatment (10mg/kg) showed synergistic reduction of Gli1 expression (&gt;90% target inhibition). We demonstrate that low-dose XRT (0.25Gy) can induce P-selectin expression specifically on medulloblastoma tumor endothelium and synergize with low-dose Fi-Vis (10mg/kg) to significantly enhance mouse survival (p&lt;0.01) compared to radiation or Fi-Vis alone. Assessment of bone toxicity using micro-CT and histological analysis following Fi-Vis administration in postnatal (P10) mice shows no bone toxicity when compared to free vismodegib. Finally, in vitro studies using bEnd.3 brain endothelial cells and in vivo studies using Cav1 knockout mice suggest a caveolin-1 mediated transcytosis mechanism for nanoparticle entry across the blood-brain barrier. CONCLUSIONS These data suggest applicability of combined XRT and tumor vasculature-targeted nanotherapeutic dose de-escalation strategies for SHH medulloblastoma with implications for other pediatric brain tumors.

scholarly journals Rho-mediated regulation of tight junctions during monocyte migration across the blood-brain barrier in HIV-1 encephalitis (HIVE)

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4770-4780 ◽  
Author(s):  
Yuri Persidsky ◽  
David Heilman ◽  
James Haorah ◽  
Marina Zelivyanskaya ◽  
Raisa Persidsky ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Rho Kinase ◽  
Dominant Negative ◽  
Brain Barrier ◽  
Monocyte Migration ◽  
Blood Brain ◽  
Hiv 1

AbstractThe blood-brain barrier (BBB) is compromised during progressive HIV-1 infection, but how this occurs is incompletely understood. We studied the integrity of tight junctions (TJs) of brain microvascular endothelial cells (BMVECs) in an in vitro BBB system and in human brain tissues with HIV-1 encephalitis (HIVE). A downregulation of TJ proteins, claudin-5 and occludin, paralleled monocyte migration into the brain during HIVE. Because small G proteins (such as Rho) can play a role in BMVEC TJ assembly, an artificial BBB system explored the relationship among TJs, Rho/Rho kinase (RhoK) activation, and transendothelial monocyte migration. Coculture of monocytes with endothelial cells led to Rho activation and phosphorylation of TJ proteins. Rho and RhoK inhibitors blocked migration of infected and uninfected monocytes. The RhoK inhibitor protected BBB integrity and reversed occludin/claudin-5 phosphorylation associated with monocyte migration. BMVEC transfection with a constitutively active mutant of RhoK led to dislocation of occludin from the membrane and loss of BMVEC cell contacts. When dominant-negative RhoK-transfected BMVECs were used in BBB constructs, monocyte migration was reduced by 84%. Thus, loss of TJ integrity was associated with Rho activation caused by monocyte brain migration, suggesting that Rho/RhoK activation in BMVECs could be an underlying cause of BBB impairment during HIVE.

scholarly journals The Blood–Brain Barrier, Oxidative Stress, and Insulin Resistance

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1695
Author(s):  
William A. Banks ◽  
Elizabeth M. Rhea
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Insulin Signaling ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Impact ◽  
Peripheral Metabolism

The blood–brain barrier (BBB) is a network of specialized endothelial cells that regulates substrate entry into the central nervous system (CNS). Acting as the interface between the periphery and the CNS, the BBB must be equipped to defend against oxidative stress and other free radicals generated in the periphery to protect the CNS. There are unique features of brain endothelial cells that increase the susceptibility of these cells to oxidative stress. Insulin signaling can be impacted by varying levels of oxidative stress, with low levels of oxidative stress being necessary for signaling and higher levels being detrimental. Insulin must cross the BBB in order to access the CNS, levels of which are important in peripheral metabolism as well as cognition. Any alterations in BBB transport due to oxidative stress at the BBB could have downstream disease implications. In this review, we cover the interactions of oxidative stress at the BBB, how insulin signaling is related to oxidative stress, and the impact of the BBB in two diseases greatly affected by oxidative stress and insulin resistance: diabetes mellitus and Alzheimer’s disease.

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