Changes in brain microvessel endothelial cell monolayer permeability induced by adrenergic drugs

Borges, Nuno; Shi, Fenglin; Azevedo, Isabel; Audus, Kenneth L.

doi:10.1016/0922-4106(94)90092-2

Cited by 51 publications

(31 citation statements)

References 17 publications

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“…Epinephrine is known to modulate endocytotic activity of the BBB, leading to changes in BBB permeability in vivo and in vitro (13,14). Although epinephrine may stimulate fluid-phase pinocytosis, this process would be nonspecific and not receptormediated.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been reported that ␣-and ␤-adrenoceptors mediate changes in the permeability in bovine brain microvessel endothelial cells, an in vitro model of the BBB. Both ␣-and ␤-adrenoreceptormediated changes in permeability are abolished by inhibiting fluid-phase pinocytosis (13,14).If the transport mechanism across the BBB for a lysosomal enzyme, which is operative in neonates, could be restored, lysosomal enzymes containing the M6P moiety might be delivered into the brain at therapeutically effective levels, in which case CNS storage diseases could be treated. Here, we report the restoration of M6P receptor-mediated transport of the lysosomal enzyme GUS at the adult BBB by pharmacological manipulation with epinephrine.…”

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confidence: 99%

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confidence: 99%

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Epinephrine enhances lysosomal enzyme delivery across the blood–brain barrier by up-regulation of the mannose 6-phosphate receptor

Urayama

Grubb

Banks

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Delivering therapeutic levels of lysosomal enzymes across the blood-brain barrier (BBB) has been a pivotal issue in treating CNS storage diseases, including the mucopolysaccharidoses. An inherited deficiency of ␤-glucuronidase (GUS) causes mucopolysaccharidosis type VII that is characterized by increased systemic and CNS storage of glycosaminoglycans. We previously showed that the neonate uses the mannose 6-phosphate (M6P) receptor to transport phosphorylated GUS (P-GUS) across the BBB and that this transporter is lost with maturation. Induction of expression of this BBB transporter would make enzyme replacement therapy in the adult possible. Here, we tested pharmacological manipulation with epinephrine to restore functional transport of P-GUS across the adult BBB. Epinephrine (40 nmol) coinjected i.v. with 131 I-P-GUS induced the transport across the BBB in 8-week-old mice. The brain influx rate of 131 I-P-GUS (0.29 l/g per min) returned to the level seen in neonates. Capillary depletion showed that 49% of the 131 I-P-GUS in brain was in brain parenchyma. No increases of influx rate or the vascular space for 125 I-albumin, a vascular marker, was observed with epinephrine (40 nmol), showing that enhanced passage was not caused by disruption of the BBB. Brain uptake of 131 I-P-GUS was significantly inhibited by M6P in a dose-dependent manner, whereas epinephrine failed to increase brain uptake of nonphosphorylated GUS. Thus, the effect of epinephrine on the transport of 131 I-P-GUS was ligand specific. These results indicate that epinephrine restores the M6P receptor-mediated functional transport of 131 I-P-GUS across the BBB in adults to levels seen in the neonate.␤-glucuronidase ͉ drug delivery ͉ enzyme replacement therapy ͉ lysosomal storage disease ͉ phosphorylated ␤-glucuronidase M ucopolysaccharidosis type VII (MPS VII) is characterized by abnormal lysosomal storage of glycosaminoglycans (GAGs) in most tissues including the CNS. MPS VII is caused by an inherited deficiency of ␤-glucuronidase (␤-D-glucuronoside glucuronosohydrolase; EC 3.2.1.31) (GUS), an enzyme that cleaves glucuronic acid residues from nonreducing termini of GAGs. Enzyme replacement therapy (ERT) with murine or human GUS in MPS VII mice reduces visceral lysosomal storage, normalizes the pathological phenotype, and prolongs lifespan (1-3). It also improves abnormal storage in brain if treatment with GUS is begun before 2 weeks of age (2, 4). Delivering the enzyme to treat CNS storage disease has been a key problem because the blood-brain barrier (BBB) restricts the passage into brain of exogenously administrated enzymes. In a prior study, we found that human phosphorylated GUS (P-GUS) is transported across the neonatal BBB by mannose 6-phosphate (M6P) receptor-mediated transcytosis, and that this transport mechanism is progressively lost with maturation so that, by 7 weeks, mice have little or no transport left (5). Thus, alterations in the transport of a lysosomal enzyme across the BBB occur with postnatal development, which limits the eff...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Epinephrine enhances lysosomal enzyme delivery across the blood–brain barrier by up-regulation of the mannose 6-phosphate receptor

Urayama

Grubb

Banks

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Another disadvantage of C6 glioma cells is that they may result in a tumour-like BBB rather than a healthy BBB (de Boer et al, 1999). Other groups have also shown an improvement in the BBB properties with the use of cAMP stimulants (Deli et al, 1995;Rubin et al, 1991), vasoactive peptides (Guillot and Audus, 1991), glucocorticoids such as hydrocortisone (Antonetti et al, 2002;Calabria et al, 2006;Hoheisel et al, 1998), and adrenergic agonists (Borges et al, 1994). In order to develop in vitro models that are more and more similar to the in vivo BBB, models have also been developed with a third cellular type, such as neurons (Schiera et al, 2005) or pericytes (Nakagawa et al, 2007).…”

Section: Primary or Low Passage Brain Capillary Endothelial Cell Cultmentioning

confidence: 99%

In vitro blood brain barrier models as a screening tool for colloidal drug delivery systems and other nanosystems

Garcel

Martel

Carrupt

et al. 2010

IJBNN

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The brain is one of the least accessible organs of the body due to the presence of the blood-brain barrier (BBB), thus making drug delivery to the brain quite a challenge. Various strategies have been explored to circumvent this physiological barrier, including the use of colloidal carriers. These carriers hold great promise as they may increase the delivery of drugs into the brain by protecting them from degradation and prolonging their circulation in the blood, as well as promoting their transport through the BBB. Moreover, functionalisation of these carriers with various ligands allows specific targeting of the central nervous system compartment. Additionally, various in vitro BBB models have been developed and are increasingly useful for screening of drug delivery systems, especially cell-based models that provide mechanistic information. In fact, this paper specifically reviews selected in vitro BBB models as a screening tool for drug delivery colloidal systems.Keywords: drug delivery; colloidal systems; nanocarriers; nanoparticles; liposomes; micelles; blood-brain barrier; BBB; in vitro model.Reference to this paper should be made as follows: Garcel, A., Martel, S., Carrupt, P.A., Doelker, E. and Delie, F. (2010) 'In vitro blood brain barrier models as a screening tool for colloidal drug delivery systems and other nanosystems', Int.

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“…In the same study, it was found that pre-treatment of the endothelial monolayers with astrocyte-conditioned medium resulted in a 30% reduction in sucrose transport through the BBB as a result of the increase in number and size of intercellular tight junctions induced by the astrocyte-conditioned medium (Tao-Cheng et al 1987;Pardridge et al 1990). Others have also shown an improvement in the barrier properties of BBEC cultures with the use of cAMP stimulants (Deli et al 1995), vasoactive peptides (Guillot & Audus 1991), and adrenergic agonists (Borges et al 1994).…”

Section: Bovine Brain Endothelial Cell Culturementioning

confidence: 99%

Untitled

2006

Journal of Pharmacy and Pharmacology

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Much research has focussed on the development of novel therapeutic agents to target various central nervous system disorders, however less attention has been given to determining the potential of such agents to permeate the blood-brain barrier (BBB), a factor that will ultimately govern the effectiveness of these agents in man. In order to assess the potential for novel compounds to permeate the BBB, various in-vitro, in-vivo and in-silico methods may be employed. Although in-vitro models (such as primary cell culture and immortalized cell lines) are useful as a screening method and can appropriately rank compounds in order of BBB permeability, they often correlate poorly to in-vivo brain uptake due to down-regulation of some BBB-specific transporters. In-vivo models (such as the internal carotid artery single injection or perfusion, intravenous bolus injection, brain efflux index and intracerebral microdialysis) provide more accurate information regarding brain uptake, and these can be complemented with novel imaging techniques (such as magnetic resonance imaging and positron emission tomography), although such methods are not suited to high-throughput permeability assessment. This paper reviews current methods used for assessing BBB permeability and highlights the particular advantages and disadvantages associated with each method, with a particular focus on methods suitable for moderate-to high-throughput screening.

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Changes in brain microvessel endothelial cell monolayer permeability induced by adrenergic drugs

Cited by 51 publications

References 17 publications

Epinephrine enhances lysosomal enzyme delivery across the blood–brain barrier by up-regulation of the mannose 6-phosphate receptor

Epinephrine enhances lysosomal enzyme delivery across the blood–brain barrier by up-regulation of the mannose 6-phosphate receptor

In vitro blood brain barrier models as a screening tool for colloidal drug delivery systems and other nanosystems

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