TY - JOUR
T1 - Molecular mechanism of ultrasound interaction with a blood brain barrier model
AU - Man, Viet Hoang
AU - Li, Mai Suan
AU - Derreumaux, Philippe
AU - Wang, Junmei
AU - Nguyen, Toan T.
AU - Nangia, S.
AU - Nguyen, Phuong H.
N1 - Funding Information:
ACKNOWLEDGMENTSThis work was supported by the Department of Science and Technology at Ho Chi Minh City, Vietnam (Grant No. 10/2018/HD-KHCNTT), the CNRS, the World Bank, the Vietnam Ministry of Science and Technology FIRST project (Grant No. 13/FIRST/1.a/VNU1), the Polish Narodowym Centrum Nauki (NCN, Grant No. 2019/35/B/ST4/02086), the National Science Foundation (NSF, Grant No. SI2-SEE-1534941), the National Institutes of Health (Grant No. NIH-R01GM118508), and the CINES center for providing computer facilities (Project No. A0080711440).
Funding Information:
This work was supported by the Department of Science and Technology at Ho Chi Minh City, Vietnam (Grant No. 10/2018/HD-KHCNTT), the CNRS, the World Bank, the Vietnam Ministry of Science and Technology FIRST project (Grant No. 13/FIRST/1.a/VNU1), the Polish Narodowym Centrum Nauki (NCN, Grant No. 2019/35/B/ST4/02086), the National Science Foundation (NSF, Grant No. SI2-SEE-1534941), the National Institutes of Health (Grant No. NIH-R01GM118508), and the CINES center for providing computer facilities (Project No. A0080711440).
Publisher Copyright:
© 2020 Author(s).
PY - 2020/7/28
Y1 - 2020/7/28
N2 - The brain is strictly protected by the blood brain barrier preventing the crossing of therapeutics to treat brain diseases. The high and low intensity focused ultrasound methods have been used to temporarily open the blood brain barrier, facilitating the transport of drugs. The methods are very promising because the opening is transient, localized, and noninvasive. However, the molecular mechanism of the opening is unknown, and this limits the development and application of these methods. With this in mind, we carry out a molecular dynamics simulation study to understand the interaction of ultrasound with the cell membrane and the tight junction. Our minimal blood brain barrier model is composed of two lipid bilayers, mimicking two portions of neighboring cells, connected together by a tight junction formed by a pair of two cis-dimers of the claudin-5 protein. Using an experimental ultrasound frequency of 50 MHz, simulations show that at low intensities, ultrasound does not impact the structure of the cell membranes and tight junction, implying that the direct interaction of ultrasound with the blood brain barrier is not responsible for the experimentally observed opening. At high intensities, the ultrasound pulls the monolayers of individual cell membrane lipid bilayers apart, creating air compartments inside the bilayers. This reduces the free energy barrier for the translocation of drugs across the lipid bilayer and enhances drug permeability. At very high intensities, the two monolayers are largely separated, resulting in cell damage and implying that the blood brain barrier is primarily opened at the experimentally observed damaged areas.
AB - The brain is strictly protected by the blood brain barrier preventing the crossing of therapeutics to treat brain diseases. The high and low intensity focused ultrasound methods have been used to temporarily open the blood brain barrier, facilitating the transport of drugs. The methods are very promising because the opening is transient, localized, and noninvasive. However, the molecular mechanism of the opening is unknown, and this limits the development and application of these methods. With this in mind, we carry out a molecular dynamics simulation study to understand the interaction of ultrasound with the cell membrane and the tight junction. Our minimal blood brain barrier model is composed of two lipid bilayers, mimicking two portions of neighboring cells, connected together by a tight junction formed by a pair of two cis-dimers of the claudin-5 protein. Using an experimental ultrasound frequency of 50 MHz, simulations show that at low intensities, ultrasound does not impact the structure of the cell membranes and tight junction, implying that the direct interaction of ultrasound with the blood brain barrier is not responsible for the experimentally observed opening. At high intensities, the ultrasound pulls the monolayers of individual cell membrane lipid bilayers apart, creating air compartments inside the bilayers. This reduces the free energy barrier for the translocation of drugs across the lipid bilayer and enhances drug permeability. At very high intensities, the two monolayers are largely separated, resulting in cell damage and implying that the blood brain barrier is primarily opened at the experimentally observed damaged areas.
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U2 - 10.1063/5.0010667
DO - 10.1063/5.0010667
M3 - Article
C2 - 32752695
AN - SCOPUS:85089018347
SN - 0021-9606
VL - 153
JO - Journal of Chemical Physics
JF - Journal of Chemical Physics
IS - 4
M1 - 045104
ER -