A Physiological Barrier Distal to the Anatomic Blood-Brain Barrier in a Model of Transvascular Delivery
Leslie L. Muldoona,
Michael A. Pagela,
Robert A. Krolla,
Simon Roman-Goldsteina,
Russell S. Jonesa and
Edward A. Neuwelt,a
a From the Departments of Cell and Developmental Biology (L.L.M.), Neurology (L.L.M., R.A.K., E.A.N.), Radiology (S.R-G.), and Pathology (R.S.J.), and the Division of Neurosurgery (E.A.N.), Oregon Health Sciences University, Portland; and The Veterans Administration Medical Center, Portland, (M.A.P., E.A.N.).
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FIG 1. MR imaging of transvascular delivery of Feridex and MION in the rat brain.
A, T1-weighted image obtained 24 hours after osmotic BBB disruption and intracarotid administration of Feridex (10 mg Fe/kg) shows enhancement in the right cerebral hemisphere.
B, T1-weighted image 24 hours after administration of MION (10 mg Fe/kg) with BBB disruption. The disrupted right cerebral hemisphere (R) enhances (white) with iron, while the left hemisphere (L) shows the noncontrast-enhanced rat brain.
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FIG 2. Light microscopy of transvascular delivery of iron oxide particles in the rat brain.
A, Histochemical staining for iron after delivery of Feridex (10 mg Fe/kg) with BBB disruption. Iron staining is increased in the disrupted right cerebral hemisphere compared with the contralateral nondisrupted left hemisphere, or saline controls. V = ventricle, LC = left corpus callosum and ventricle, RC = right corpus callosum (original magnification x20).
B, Capillary staining for iron in right cerebral hemisphere after Feridex delivery with BBB disruption is indicated by arrowheads. Arrows indicate staining of red blood cells (original magnification x50).
C, Histochemical staining for iron in rat brain 2 hours after delivery of MION (10 mg Fe/kg) with BBB disruption shows an increase in iron staining in the disrupted right cerebral hemisphere (RH) compared with the nondisrupted left hemisphere (LH). V indicates the ventricle (original magnification x20).
D, Cellular staining for iron (arrows) is widespread in the right cerebral hemisphere 24 hours after delivery of 10 mg/kg MION with BBB disruption. Arrowheads indicate capillary staining (original magnification x100).
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FIG 3. A–E, Electron microscopy of transvascular delivery of iron particles. Rat brain micrographs after BBB disruption-enhanced delivery of Feridex are shown in A (original magnification x19,000), B (original magnification x48,000), and C (original magnification x87,000). Electron-dense particles (arrows) are located around capillaries, adjacent to the basement membrane (BM) and pericapillary pericyte (P). L = capillary lumen, MA = myelinated axon, EC = capillary endothelial cell. Location of MION after BBB disruption is shown in D (original magnification x65,000) and E (original magnification x36,700). Electron-dense MION particles (D, arrows) were found near synapses (S) and mitochondria (Mt). MION particles were detected in pericapillary pericytes (P) and in what appear to be pericyte processes (E, arrow). EC = capillary endothelial cell, RBC = red blood cell, BM = basement membrane
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