Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary Mechanisms
<b>Background/Objective:</b> The blood–brain barrier (BBB) is selectively permeable, but it also poses significant challenges for treating CNS diseases. Low-intensity focused ultrasound (LiFUS), paired with microbubbles is a promising, non-invasive technique for transiently opening the B...
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2025-01-01
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| author | Tasneem A. Arsiwala Kathryn E. Blethen Cullen P. Wolford Geoffrey L. Pecar Dhruvi M. Panchal Brooke N. Kielkowski Peng Wang Manish Ranjan Jeffrey S. Carpenter Victor Finomore Ali Rezai Paul R. Lockman |
| author_facet | Tasneem A. Arsiwala Kathryn E. Blethen Cullen P. Wolford Geoffrey L. Pecar Dhruvi M. Panchal Brooke N. Kielkowski Peng Wang Manish Ranjan Jeffrey S. Carpenter Victor Finomore Ali Rezai Paul R. Lockman |
| author_sort | Tasneem A. Arsiwala |
| collection | DOAJ |
| description | <b>Background/Objective:</b> The blood–brain barrier (BBB) is selectively permeable, but it also poses significant challenges for treating CNS diseases. Low-intensity focused ultrasound (LiFUS), paired with microbubbles is a promising, non-invasive technique for transiently opening the BBB, allowing enhanced drug delivery to the central nervous system (CNS). However, the downstream physiological effects following BBB opening, particularly secondary responses, are not well understood. This study aimed to characterize the time-dependent changes in BBB permeability, transporter function, and inflammatory responses in both sonicated and non-sonicated brain tissues following LiFUS treatment. <b>Methods:</b> We employed in situ brain perfusion to assess alterations in BBB integrity and transporter function, as well as multiplex cytokine analysis to quantify the inflammatory response. <b>Results:</b> Our findings show that LiFUS significantly increased vascular volume and glucose uptake, with reduced P-gp function in brain tissues six hours post treatment, indicating biphasic BBB disruption. Additionally, elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6, were observed in both sonicated and non-sonicated regions. A comparative analysis between wild-type and immunodeficient mice revealed distinct patterns of cytokine release, with immunodeficient mice showing lower serum concentrations of IFN-γ and TNF-α, highlighting the potential impact of immune status on the inflammatory response to LiFUS. <b>Conclusions:</b> This study provides new insights into the biphasic nature of LiFUS-induced BBB disruption, emphasizing the importance of understanding the timing and extent of secondary physiological changes. |
| format | Article |
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| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-5f612956ca3145abbd5adbd66923c1a72025-01-24T13:45:50ZengMDPI AGPharmaceutics1999-49232025-01-011717510.3390/pharmaceutics17010075Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary MechanismsTasneem A. Arsiwala0Kathryn E. Blethen1Cullen P. Wolford2Geoffrey L. Pecar3Dhruvi M. Panchal4Brooke N. Kielkowski5Peng Wang6Manish Ranjan7Jeffrey S. Carpenter8Victor Finomore9Ali Rezai10Paul R. Lockman11Department of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV 26505, USADepartment of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV 26505, USADepartment of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV 26505, USADepartment of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV 26505, USADepartment of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV 26505, USADepartment of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV 26505, USADepartment of Neuroscience, West Virginia University School of Medicine, Rockefeller Neuroscience Institute, Morgantown, WV 26505, USADepartment of Neuroscience, West Virginia University School of Medicine, Rockefeller Neuroscience Institute, Morgantown, WV 26505, USADepartment of Neuroscience, West Virginia University School of Medicine, Rockefeller Neuroscience Institute, Morgantown, WV 26505, USADepartment of Neuroscience, West Virginia University School of Medicine, Rockefeller Neuroscience Institute, Morgantown, WV 26505, USADepartment of Neuroscience, West Virginia University School of Medicine, Rockefeller Neuroscience Institute, Morgantown, WV 26505, USADepartment of Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV 26505, USA<b>Background/Objective:</b> The blood–brain barrier (BBB) is selectively permeable, but it also poses significant challenges for treating CNS diseases. Low-intensity focused ultrasound (LiFUS), paired with microbubbles is a promising, non-invasive technique for transiently opening the BBB, allowing enhanced drug delivery to the central nervous system (CNS). However, the downstream physiological effects following BBB opening, particularly secondary responses, are not well understood. This study aimed to characterize the time-dependent changes in BBB permeability, transporter function, and inflammatory responses in both sonicated and non-sonicated brain tissues following LiFUS treatment. <b>Methods:</b> We employed in situ brain perfusion to assess alterations in BBB integrity and transporter function, as well as multiplex cytokine analysis to quantify the inflammatory response. <b>Results:</b> Our findings show that LiFUS significantly increased vascular volume and glucose uptake, with reduced P-gp function in brain tissues six hours post treatment, indicating biphasic BBB disruption. Additionally, elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6, were observed in both sonicated and non-sonicated regions. A comparative analysis between wild-type and immunodeficient mice revealed distinct patterns of cytokine release, with immunodeficient mice showing lower serum concentrations of IFN-γ and TNF-α, highlighting the potential impact of immune status on the inflammatory response to LiFUS. <b>Conclusions:</b> This study provides new insights into the biphasic nature of LiFUS-induced BBB disruption, emphasizing the importance of understanding the timing and extent of secondary physiological changes.https://www.mdpi.com/1999-4923/17/1/75blood–brain barrier (BBB) disruptionlow-intensity focused ultrasound (LiFUS)P-glycoprotein (P-gp)vascular permeabilityneuroinflammation |
| spellingShingle | Tasneem A. Arsiwala Kathryn E. Blethen Cullen P. Wolford Geoffrey L. Pecar Dhruvi M. Panchal Brooke N. Kielkowski Peng Wang Manish Ranjan Jeffrey S. Carpenter Victor Finomore Ali Rezai Paul R. Lockman Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary Mechanisms Pharmaceutics blood–brain barrier (BBB) disruption low-intensity focused ultrasound (LiFUS) P-glycoprotein (P-gp) vascular permeability neuroinflammation |
| title | Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary Mechanisms |
| title_full | Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary Mechanisms |
| title_fullStr | Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary Mechanisms |
| title_full_unstemmed | Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary Mechanisms |
| title_short | Single Exposure to Low-Intensity Focused Ultrasound Causes Biphasic Opening of the Blood-Brain Barrier Through Secondary Mechanisms |
| title_sort | single exposure to low intensity focused ultrasound causes biphasic opening of the blood brain barrier through secondary mechanisms |
| topic | blood–brain barrier (BBB) disruption low-intensity focused ultrasound (LiFUS) P-glycoprotein (P-gp) vascular permeability neuroinflammation |
| url | https://www.mdpi.com/1999-4923/17/1/75 |
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