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Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium.
Ultrasound Med Biol 2008; 34(7):1093-104UM

Abstract

Previous studies have investigated a potential method for targeted drug delivery in the central nervous system that uses focused ultrasound bursts combined with an ultrasound contrast agent to temporarily disrupt the blood-brain barrier (BBB). The purpose of this work was to investigate the integrity of the tight junctions (TJs) in rat brain microvessels after this BBB disruption. Ultrasound bursts (1.5-MHz) in combination with a gas contrast agent (Optison) was applied at two locations in the brain in 25 rats to induce BBB disruption. Using immunoelectron microscopy, the distributions of the TJ-specific transmembrane proteins occludin, claudin-1, claudin-5, and of submembranous ZO-1 were examined at 1, 2, 4, 6 and 24 h after sonication. A quantitative evaluation of the protein expression was made by counting the number of immunosignals per micrometer in the junctional clefts. BBB disruption at the sonicated locations was confirmed by the leakage of i.v. administered horseradish peroxidase (HRP, m.w. 40,000 Da) and lanthanum chloride (La(3+), m.w. approximately 139 Da). Leakage of these agents was observed at 1 and 2 h and, in a few vessels, at 4 h after ultrasound application. These changes were paralleled by the apparent disintegration of the TJ complexes, as evidenced by the redistribution and loss of the immunosignals for occludin, claudin-5 and ZO-1. Claudin-1 seemed less involved. At 6 and 24 h after sonication, no HRP or lanthanum leakage was observed and the barrier function of the TJs, as indicated by the localization and density of immunosignals, appeared to be completely restored. This study provides the first direct evidence that ultrasound bursts combined with a gas contrast agent cause disassembling of the TJ molecular structure, leading to loss of the junctional barrier functions in brain microvessels. The BBB disruption appears to last up to 4 h after sonication and permits the paracellular passage of agents with molecular weights up to at least 40 kDa. These promising features can be exploited in the future development of this method that could enable the delivery of drugs, antibodies or genes to targeted locations in the brain.

Authors+Show Affiliations

Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18378064

Citation

Sheikov, Nickolai, et al. "Effect of Focused Ultrasound Applied With an Ultrasound Contrast Agent On the Tight Junctional Integrity of the Brain Microvascular Endothelium." Ultrasound in Medicine & Biology, vol. 34, no. 7, 2008, pp. 1093-104.
Sheikov N, McDannold N, Sharma S, et al. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol. 2008;34(7):1093-104.
Sheikov, N., McDannold, N., Sharma, S., & Hynynen, K. (2008). Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound in Medicine & Biology, 34(7), pp. 1093-104. doi:10.1016/j.ultrasmedbio.2007.12.015.
Sheikov N, et al. Effect of Focused Ultrasound Applied With an Ultrasound Contrast Agent On the Tight Junctional Integrity of the Brain Microvascular Endothelium. Ultrasound Med Biol. 2008;34(7):1093-104. PubMed PMID: 18378064.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. AU - Sheikov,Nickolai, AU - McDannold,Nathan, AU - Sharma,Shipra, AU - Hynynen,Kullervo, Y1 - 2008/04/18/ PY - 2007/05/11/received PY - 2007/12/12/revised PY - 2007/12/19/accepted PY - 2008/4/2/pubmed PY - 2008/10/1/medline PY - 2008/4/2/entrez SP - 1093 EP - 104 JF - Ultrasound in medicine & biology JO - Ultrasound Med Biol VL - 34 IS - 7 N2 - Previous studies have investigated a potential method for targeted drug delivery in the central nervous system that uses focused ultrasound bursts combined with an ultrasound contrast agent to temporarily disrupt the blood-brain barrier (BBB). The purpose of this work was to investigate the integrity of the tight junctions (TJs) in rat brain microvessels after this BBB disruption. Ultrasound bursts (1.5-MHz) in combination with a gas contrast agent (Optison) was applied at two locations in the brain in 25 rats to induce BBB disruption. Using immunoelectron microscopy, the distributions of the TJ-specific transmembrane proteins occludin, claudin-1, claudin-5, and of submembranous ZO-1 were examined at 1, 2, 4, 6 and 24 h after sonication. A quantitative evaluation of the protein expression was made by counting the number of immunosignals per micrometer in the junctional clefts. BBB disruption at the sonicated locations was confirmed by the leakage of i.v. administered horseradish peroxidase (HRP, m.w. 40,000 Da) and lanthanum chloride (La(3+), m.w. approximately 139 Da). Leakage of these agents was observed at 1 and 2 h and, in a few vessels, at 4 h after ultrasound application. These changes were paralleled by the apparent disintegration of the TJ complexes, as evidenced by the redistribution and loss of the immunosignals for occludin, claudin-5 and ZO-1. Claudin-1 seemed less involved. At 6 and 24 h after sonication, no HRP or lanthanum leakage was observed and the barrier function of the TJs, as indicated by the localization and density of immunosignals, appeared to be completely restored. This study provides the first direct evidence that ultrasound bursts combined with a gas contrast agent cause disassembling of the TJ molecular structure, leading to loss of the junctional barrier functions in brain microvessels. The BBB disruption appears to last up to 4 h after sonication and permits the paracellular passage of agents with molecular weights up to at least 40 kDa. These promising features can be exploited in the future development of this method that could enable the delivery of drugs, antibodies or genes to targeted locations in the brain. SN - 0301-5629 UR - https://www.unboundmedicine.com/medline/citation/18378064/Effect_of_focused_ultrasound_applied_with_an_ultrasound_contrast_agent_on_the_tight_junctional_integrity_of_the_brain_microvascular_endothelium_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0301-5629(07)00659-X DB - PRIME DP - Unbound Medicine ER -