Dataset Information

Angiogenic response of rat hippocampal vasculature to focused ultrasound-mediated increases in blood-brain barrier permeability.

ABSTRACT: Focused ultrasound (FUS) and circulating microbubbles can induce a targeted and transient increase in blood-brain barrier permeability. While preclinical research has demonstrated the utility of FUS for efficacious drug deliver to the brain, there remain gaps in our knowledge regarding the long-term response of brain vasculature to this intervention. Previous work has demonstrated transcriptional changes in hippocampal microvessels following sonication that are indicative of the initiation of angiogenic processes. Moreover, blood vessel growth has been reported in skeletal muscle following application of FUS and microbubbles. The current study demonstrates that blood vessel density in the rat hippocampus is modestly elevated at 7 and 14 d post-FUS compared to the contralateral hemisphere (7 d: 10.9?±?6.0%, p?=?0.02; 14 d: 12.1?±?3.2%, p?

SUBMITTER: McMahon D

PROVIDER: S-EPMC6093874 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Angiogenic response of rat hippocampal vasculature to focused ultrasound-mediated increases in blood-brain barrier permeability.

McMahon Dallan D Mah Ethan E Hynynen Kullervo K

Scientific reports 20180815 1

Focused ultrasound (FUS) and circulating microbubbles can induce a targeted and transient increase in blood-brain barrier permeability. While preclinical research has demonstrated the utility of FUS for efficacious drug deliver to the brain, there remain gaps in our knowledge regarding the long-term response of brain vasculature to this intervention. Previous work has demonstrated transcriptional changes in hippocampal microvessels following sonication that are indicative of the initiation of an ...[more]

PMID: 30111814

Similar Datasets

Project description:BACKGROUND:The persistence of adult hippocampal neurogenesis (AHN) is sharply decreased in Alzheimer's disease (AD). The neuropathologies of AD include the presence of amyloid-? deposition in plaques, tau hyperphosphorylation in neurofibrillary tangles, and cholinergic system degeneration. The focused ultrasound (FUS)-mediated blood-brain barrier opening modulates tau hyperphosphorylation, the accumulation of amyloid-? proteins, and increases in AHN. However, it remains unclear whether FUS can modulate AHN in cholinergic-deficient conditions. In this study, we investigated the effect of FUS on AHN in a cholinergic degeneration rat model of dementia. METHODS:Adult male Sprague-Dawley rats (n?=?48; 200-250?g) were divided into control (phosphate-buffered saline injection), 192 IgG-saporin (SAP), and SAP+FUS groups; in the two latter groups, SAP was injected bilaterally into the lateral ventricle. We applied FUS to the bilateral hippocampus with microbubbles. Immunohistochemistry, enzyme-linked immunosorbent assay, immunoblotting, 5-bromo-2'-deoxyuridine labeling, an acetylcholinesterase assay, and the Morris water maze test were performed to assess choline acetyltransferase, acetylcholinesterase activity, brain-derived neurotrophic factor expression, neural proliferation, and spatial memory, respectively. Statistical significance of differences in between groups was calculated using one-way and two-way analyses of variance followed by Tukey's multiple comparison test to determine the individual and interactive effects of FUS on immunochemistry and behavioral analysis. P?<?0.05 was considered significant. RESULTS:Cholinergic degeneration in rats significantly decreased the number of choline acetyltransferase neurons (P?<?0.05) in the basal forebrain, as well as AHN and spatial memory function. Rats that underwent FUS-mediated brain-blood barrier opening exhibited significant increases in brain-derived neurotrophic factor (BDNF; P?<?0.05), early growth response protein 1 (EGR1) (P?<?0.01), AHN (P?<?0.01), and acetylcholinesterase activity in the frontal cortex (P?<?0.05) and hippocampus (P?<?0.01) and crossing over (P?<?0.01) the platform in the Morris water maze relative to the SAP group after sonication. CONCLUSIONS:FUS treatment increased AHN and improved spatial memory. This improvement was mediated by increased hippocampal BDNF and EGR1. FUS treatment may also restore AHN and protect against neurodegeneration, providing a potentially powerful therapeutic strategy for AD.

Project description:Rationale: Focused ultrasound (FUS), in conjunction with circulating microbubbles (MBs), can be used to transiently increase the permeability of the blood-brain barrier (BBB) in a targeted manner, allowing therapeutic agents to enter the brain from systemic circulation. While promising preclinical work has paved the way for the initiation of 3 human trials, there remains concern regarding neuroinflammation following treatment. The aim of this study was to assess the magnitude of this response following sonication and explore the influence of MB dose. Methods: Differential expression of NF?B signaling pathway genes was assessed in rats at 6 h and 4 days following a FUS-mediated increase in BBB permeability. Three sonication schemes were tested: (1) a clinical imaging dose of MBs + peak negative pressure (PNP) controlled by acoustic feedback, (2) 10x clinical imaging dose of MBs + constant PNP of 0.290 MPa, and (3) 10x clinical imaging dose of MBs + PNP controlled by acoustic feedback. Follow-up magnetic resonance imaging (MRI) was performed to assess edema and hemorrhage. Hematoxylin and eosin histology was used to evaluate general tissue health. Results: MB dose has a significant impact on the expression of several key genes involved in acute inflammation and immune activation, including Tnf, Birc3, and Ccl2. At a clinical imaging dose of MBs, there were no significant changes detected in the expression of any NF?B signaling pathway genes. Conversely, a high MB dose resulted in a clear activation of the NF?B signaling pathway, accompanied by edema, neuronal degeneration, neutrophil infiltration, and microhemorrhage. Results also suggest that post-FUS gadolinium enhancement may hold predictive value in assessing the magnitude of inflammatory response. Conclusion: While a significant and damaging inflammatory response was observed at high MB doses, it was demonstrated that FUS can be used to induce increased BBB permeability without an associated upregulation of NF?B signaling pathway gene expression. This emphasizes the importance of employing optimized FUS parameters to mitigate the chances of causing injury to the brain at the targeted locations.

Dataset Information

Angiogenic response of rat hippocampal vasculature to focused ultrasound-mediated increases in blood-brain barrier permeability.

Publications

Angiogenic response of rat hippocampal vasculature to focused ultrasound-mediated increases in blood-brain barrier permeability.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets