Ultrastructural and Morphometric Investigation of Human Brain Capillaries in Normal and Peritumoral Tissues

Bertossi, M; Virgintino, Daniela; Maiorano, Eugenio; Occhiogrosso, M; Roncali, Luisa

doi:10.3109/01913129709023246

Cited by 104 publications

(61 citation statements)

References 44 publications

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“…58 These components not only provide a mechanical supporting structure for the capillary wall, they are also important as a negatively charged barrier arising from the chondroitin and heparan sulfate residues, in addition to the anionic properties of the luminal and abluminal membranes of the endothelial cells. 59 Our results suggest that adsorptive-mediated endocytosis occurs at least at the luminal side of brain capillaries. The similarity in behavior observed for the peptide vectors studied suggests that the externalization at the abluminal side of endothelial cells may also be via a receptor-independent mechanism.…”

Section: Mechanism Of Brain Uptakementioning

confidence: 79%

Peptide delivery to the brain via adsorptive-mediated endocytosis: Advances with SynB vectors

Drin¹,

Rousselle²,

Scherrmann

et al. 2002

AAPS J

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Biological membranes normally restrict the passage of hydrophilic molecules. This impairs the use of a wide variety of drugs for biomedical applications. To overcome this problem, researchers have developed strategies that involve conjugating the molecule of interest to one of a number of peptide entities that are efficiently transported across the cell membranes. In the past decade, a number of different peptide families with the ability to cross the cell membranes have been identified. Certain of these families enter the cells by a receptor-independent mechanism, are short (10-27 amino acid residues), and can deliver successfully various cargoes across the cell membrane into the cytoplasm or nucleus. Surprisingly, some of these vectors, the SynB vectors, have also shown the ability to deliver hydrophilic molecules across the blood-brain barrier, one of the major obstacles to the development of drugs to combat diseases affecting the CNS.The most important factors determining the extent to which a molecule will be delivered from the blood into the CNS are lipid solubility, molecular mass, and charge. Therefore, based simply on lipid solubility and molecular mass, any peptide-based or oligonucleotide-based neuropharmaceutical will almost certainly be impeded by the BBB. To overcome the limited access of drugs to the brain, at least 3 strategies have been developed that achieve BBB penetration 2-5 :1. Neurosurgery-based strategies, which bypass the BBB by means of intraventricular drug infusion, intracerebral infusion, or disruption of the BBB; 2. Pharmacology-based strategies, some examples of which employ lipidation, or chemical modification of the drug to improve its ability to diffuse across the BBB; and KEYWORDS: intracellular delivery, peptide vector, blood-brain barrier, multidrug resistance. 3. Physiology-based strategies, which take advantage of BBB nutrient carriers or specific receptors, mediating transport via these transporter systems. One example has been to conjugate the therapeutic drug with a protein or a monoclonal antibody that gains access to the brain by either receptor -or adsorptive-mediated transcytosis (eg, transferrin receptor-mediated transfer).2

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Section: Mechanism Of Brain Uptakementioning

confidence: 79%

Peptide delivery to the brain via adsorptive-mediated endocytosis: Advances with SynB vectors

Drin¹,

Rousselle²,

Scherrmann

et al. 2002

AAPS J

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“…In semithin sections, vessels were seen as randomly oriented vascular pro les. ECs, some of which were relatively normal, exhibited the ultrastructural spectrum of nonspeci c abnormalities known to occur in capillaries of primary and metastatic CNS tumors (Bertossi et al, 1997;Shibata, 1989), which were observed in both the gliomas and lymphomas in our study sample. These included marked irregularity of lumen size, with blebs and vesicles being either partially attached or free-oating in occulent material containing cell debris.…”

Section: Morphology Of Capillary Endothelium: Nonspeci C Changesmentioning

confidence: 93%

“…7). Increased electron lucency, presumably due to activation of capillary ECs and pericytes and accompanied by an increase in abluminal endocytosis, has been observed in peritumoral regions of anaplastic gliomas (Bertossi et al, 1997).Our study is morphologic and descriptive. On that basis alone, the ECs of PCNSLs are distinctive and are different from the ECs of other brain tumors.…”

mentioning

confidence: 91%

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The blood-brain barrier in primary CNS lymphomas: Ultrastructural evidence of endothelial cell death

Molnár

O’Neill²,

Scheithauer

et al. 1999

Neuro-Oncology

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The vasculature of 24 primary CNS B-cell lymphomas that were not related to acquired immunode ciency syndrome was systematically studied by electron microscopy. Seven low-grade astrocytic tumors were included for comparison. Classical electron microscopy features of apoptosis were found in lymphoma cells of 21 of 22 subjects. Capillaries of gliomas and lymphomas showed changes reported previously: variability of endothelial cell (EC)-thickness and number, basal lamina thickness and duplication, and fenestrations. Primary CNS B-cell lymphoma ECs showed two distinctive populations of electron-dense and electron-lucent cells. The electron-dense ECs occurred in 38% of all capillaries, with changes consisting of chromatin condensation in bizarre and contracted nuclei, cytoplasmic shrinkage with markedly increased electron density, and dilatation of the endoplasmic reticulum. We interpreted these changes as indicative of apoptosis. Cell death eventually resulted in complete disintegration of the endothelium with frank discontinuities of the EC component of the blood-tumor barrier in capillaries and postcapillary venules. Another population of ECs had increased cell volume, conspicuous cytoplasmic electron lucency, dispersed organelles, scattered vesicles, and apical stress bers. We interpreted these changes as indicative of cellular regeneration. Individual apoptotic ECs often lay next to normal or regenerating ECs. Neither type of EC change was observed in gliomas, which also lacked perivascular neoplastic lymphocytic cuf ng. We believe that these populations of ECs, which have not been described in other disorders affecting the bloodbrain barrier, may be induced by cytokines released from necrotic and/or apoptotic tumor lymphocytes and may explain the unusual imaging characteristics of primary CNS B-cell lymphomas treated with corticosteroids. Neuro-Oncology 1, 89-100, 1999 (Posted to NeuroOncology [serial online], Doc. 98-09, April 30, 1999 A lthough much is known about the pathobiology of PCNSLs, 3 they present a therapeutic challenge to neuro-oncologists who note a rising incidence of this once uncommon tumor (Corn et al., 1997;Grant and Isaacson, 1992;Morgello, 1995;Neuwelt et al., 1990), particularly in HIV-infected individuals (Tellez et al., 1997). When treated with corticosteroid therapy, PCNSLs will sometimes show a rapid, partial to com- Neuro-Oncology Neuro-OncologyA P R I L 1 9 9 9 90 plete disappearance of their dense, typically homogenous contrast enhancement. This response, which has been termed the "ghost tumor" phenomenon (Vaquero et al., 1984), has been studied both clinically and by quantitative measurement of BBB function (Ott et al., 1991;Pirotte et al., 1997); the frequency with which this effect occurs, the time course of its development, and the quantitative magnitude of the change have not been studied, in part because of the rarity of this tumor. This peculiarity of contrast medium uptake suggests that, in either anatomic and/or physiologic terms, the BBB in PCNSLs differs from that of oth...

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“…The peritumoral region of metastases represents vasogenic edema caused by increased interstitial water (60), in contrast to the peritumoral region of gliomas, which consists of tumoral infiltration into the brain parenchyma and accompanying neovascularity beyond the contrast-enhancing margins of the tumor (30). Due to the presence of these infiltrating tumor cells, peritumoral pMRI and sMRI of gliomas as compared to metastases show increased rCBV (1.3 Ϯ 0.9 vs. 0.4 Ϯ 0.2) and increased Cho (2.3 Ϯ 1.2 vs. 0.8 Ϯ 0.2) (19).…”

Section: Peritumoralmentioning

confidence: 99%

Brain MRI: Tumor evaluation

Young

Knopp

2006

Magnetic Resonance Imaging

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The designation "brain tumors" is commonly applied to a wide variety of intracranial mass lesions that are distinct in their location, biology, treatment, and prognosis. Since many of these lesions do not arise from brain parenchyma, the more appropriate term would be "intracranial tumors." The term "tumor" is used to include both neoplastic and non-neoplastic mass lesions, and should be considered in its broadest sense to simply indicate a space-occupying mass. This review describes an imaging-based approach for evaluating intracranial tumors. Conventional MRI is discussed in the setting of a regional classification system. This system provides a framework for analysis, and imaging clues can then be applied to narrow the differential possibilities. Emphasis is placed on advanced MRI techniques and their utility for deciphering common diagnostic problems.

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Ultrastructural and Morphometric Investigation of Human Brain Capillaries in Normal and Peritumoral Tissues

Cited by 104 publications

References 44 publications

Peptide delivery to the brain via adsorptive-mediated endocytosis: Advances with SynB vectors

Peptide delivery to the brain via adsorptive-mediated endocytosis: Advances with SynB vectors

The blood-brain barrier in primary CNS lymphomas: Ultrastructural evidence of endothelial cell death

Brain MRI: Tumor evaluation

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