Interendothelial junctional changes underlie the developmental ‘tightening’ of the blood-brain barrier

Stewart, Patricia A.; Hayakawa, Eiji

doi:10.1016/0165-3806(87)90107-6

Cited by 157 publications

(83 citation statements)

References 47 publications

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“…Although it is unclear whether the blood-retinal barrier is immature in neonatal mice just like the blood-brain barrier, immaturity of the barriers may have enabled the vector infection to occur in retinal cells. 34 Here, we also showed that lysosomal storage in corneal stroma was completely eliminated in the mice treated during the neonatal period, while no obvious efficacy was seen in the mice treated in adulthood. This finding is unexpected but favorable in terms of treatment of corneal clouding, which is the most frequent ocular manifestation in several types of mucopolysaccharidoses.…”

Section: Adenovirus Injection Into Neonatal Mice With Mspvii Y Kamatasupporting

confidence: 49%

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Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII

et al. 2003

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Systemic injection of an adenovirus vector into adult mice resulted in pathological improvements in multiple visceral organs of mice with mucopolysaccharidosis VII; however, no therapeutic efficacy was observed for mental retardation, skeletal deformities, corneal clouding, and retinal degeneration. In this study, an adenovirus vector expressing human bglucuronidase was injected into mice with mucopolysaccharidosis VII within 24 h of birth, and therapeutic efficacy was evaluated. In the brains of the mice, more than 20% of GUSB activity was maintained for at least 20 weeks after birth, and histopathological analysis showed no obvious lysosomal storage. Furthermore, no vacuolated cells were detected in corneal stroma and retinal pigment epithelium in the eyes of the mice treated in the neonatal period, while pathological improvement was not observed in adult MPSVII mice that received similar treatments. The treated mice also lacked characteristic facial skeletal deformities, and radiographic analysis demonstrated that their facial and cranial bones were morphologically normal. These results indicate that a single systemic adenovirus injection in the neonatal period could prevent the progression of mental retardation, corneal clouding, retinal degeneration, and skeletal deformities, all of which are frequently observed clinical manifestations and difficult to treat in adulthood.

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Section: Adenovirus Injection Into Neonatal Mice With Mspvii Y Kamatasupporting

confidence: 49%

“…34 The blood-retinal barrier is also a Time-dependent change of serum GUSB activity in the mice treated with AxCAhGUS. To investigate the feasibility of gene transduction by multiple vector injections, we performed periodic serum sampling from the mice infected with AxCAhGUS during the neonatal period.…”

Section: Discussionmentioning

confidence: 99%

Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII

et al. 2003

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“…A preliminary ERT trial performed in one MPS IIID goat kid had no effect on heparan sulfate levels in the brain (19); similarly, a short-term ERT trial in 3-mo-old MPS IIIB mice resulted in enzyme activity in the liver but not in the brain (20). It has been proposed that in mice, the tight junctions between the endothelial cells, which form the barrier, are incompletely formed at birth, rendering the BBB "leaky" to circulating molecules (21). Intravenous administration of ␤-glucuronidase to newborn MPS VII mice has shown enzyme accumulation to 31% normal levels in the brain (22).…”

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confidence: 99%

Enzyme-Replacement Therapy from Birth Delays the Development of Behavior and Learning Problems in Mucopolysaccharidosis Type IIIA Mice

Gliddon

Hopwood

2004

Pediatr Res

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Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome) is a lysosomal storage disorder characterized by severe CNS degeneration, resulting in behavioral abnormalities and loss of learned abilities. Early treatment is vital to prevent long-term clinical pathology in lysosomal storage disorders. We have used naturally occurring MPS IIIA mice to assess the effects of long-term enzyme-replacement therapy initiated either at birth or at 6 wk of age. MPS IIIA and normal control mice received weekly i.v. injections of 1 mg/kg recombinant human sulfamidase until 20 wk of age. Sulfamidase is able to enter the brain until the blood-brain barrier completely closes at 10 -14 d of age. MPS IIIA mice that were treated from birth demonstrated normal weight, behavioral characteristics, and ability to learn. MPS IIIA mice that were treated from birth performed significantly better in the Morris water maze than MPS IIIA mice that were treated from 6 wk of age or left untreated. A reduction in storage vacuoles in cells of the CNS in MPS IIIA mice that were treated from birth is consistent with the improvements observed. These data suggest that enzyme that enters the brain in the first few weeks of life, before the blood-brain barrier matures, is able to delay the development of behavior and learning difficulties in MPS IIIA mice. , and glucosamine-6-sulfatase (MPS IIID) (1). MPS III has an estimated incidence of 1 in 66,000 births in Australia, with MPS IIIA the most common (2). MPS III is characterized by severe CNS degeneration, resulting in progressive mental retardation. After a period of seemingly normal development, patients exhibit a range of symptoms, including rapid loss of social skills with hyperactivity and aggressive behavior, loss of learning ability, disturbed sleep patterns, hirsutism, coarse facies, and diarrhea. Death occurs in severely affected children in the mid-to late-teenage years usually as a result of respiratory infection (3). Phenotypic variation in MPS III ranges from severe to intermediate to attenuated, a result of heterogeneity at the molecular level. A total of 62 causative mutations have been identified for MPS IIIA (4).A naturally occurring mouse model of MPS IIIA has been described (5), a colony of which is established in Adelaide. Disease in the mice results from a base substitution at codon 31 in the sulfamidase gene, altering an aspartic acid to an asparagine (D31N) (6). This aspartic 31 is involved in binding of the divalent metal ion needed for catalytic function (7-9). MPS IIIA mice exhibit widespread intracellular storage in a variety of cell types. Affected mice are also reported to store secondarily gangliosides G M2 and G M3 , a feature also reported in two MPS IIIA dog models (10,11), a knock-out MPS IIIB mouse (12), and a caprine MPS IIID model (13

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“…HRP is not transcytosed within vesicles, indicating that vesicular transport may occur only rarely in brain endothelial cells. These observations have been confirmed by many electron microscopic studies, and endothelial cell characteristics such as tight junction formation, mitochondrial density, vesicle density, and transporter location have been quantitatively compared between tissues [87,88].…”

Section: Introductionmentioning

confidence: 48%

Biomedical Technologies for In Vitro Screening and Controlled Delivery of Neuroactive Compounds

Frampton¹,

Shuler²,

Shain³

et al. 2008

CNSAMC

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Cell culture models can provide information pertaining to the effective dose, toxiciology, and kinetics, for a variety of neuroactive compounds. However, many in vitro models fail to adequately predict how such compounds will perform in a living organism. At the systems level, interactions between organs can dramatically affect the properties of a compound by alteration of its biological activity or by elimination of it from the body. At the tissue level, interaction between cell types can alter the transport properties of a particular compound, or can buffer its effects on target cells by uptake, processing, or changes in chemical signaling between cells. In any given tissue, cells exist in a three-dimensional environment bounded on all sides by other cells and components of the extracellular matrix, providing kinetics that are dramatically different from the kinetics in traditional two-dimensional cell culture systems. Cell culture analogs are currently being developed to better model the complex transport and processing that occur prior to drug uptake in the CNS, and to predict blood-brain barrier permeability. These approaches utilize microfluidics, hydrogel matrices, and a variety of cell types (including lung epithelial cells, hepatocytes, adipocytes, glial cells, and neurons) to more accurately model drug transport and biological activity. Similar strategies are also being used to control both the spatial and temporal release of therapeutic compounds for targeted treatment of CNS disease.

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Interendothelial junctional changes underlie the developmental ‘tightening’ of the blood-brain barrier

Cited by 157 publications

References 47 publications

Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII

Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII

Enzyme-Replacement Therapy from Birth Delays the Development of Behavior and Learning Problems in Mucopolysaccharidosis Type IIIA Mice

Biomedical Technologies for In Vitro Screening and Controlled Delivery of Neuroactive Compounds

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