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Esma S. A., Abdurashitov A. S., Namykin A. A., Shirokov A. A., Lykova E. Y., Sarantseva E. I., Iskra T. D., Vodovozova E. L., Khorovodov A. P., Terskov A. V., Mamedova A. T., Agranovich I. M., Klimova M. M., Semyachkina-Glushkovskaya O. V. Changes in Blood-Brain Barrier Permeability under the Influence of Loud Sound. Izvestiya of Saratov University. New series. Series: Chemistry. Biology. Ecology, 2019, vol. 19, iss. 3, pp. 312-322. DOI:


Changes in Blood-Brain Barrier Permeability under the Influence of Loud Sound


The development of methods of drug delivery to the brain is one of the priorities of the therapy of most cerebral diseases. There are more than 70 technologies to overcome the blood-brain barrier (BBB), but many of them are not widely used in daily clinical practice, as they lead to negative consequences. Here we propose a new method of overcoming the BBB using loud sound (110 dB, 370 Hz, duration – 2 hours). Independent results on mice obtained in several experimental groups clearly demonstrate that sound significantly increases the permeability of BBB to high-molecular substances, as well as to liposomes (100 nm) simulating the delivery to the brain of solutes, proteins and materials with nanocarriers. Sound-induced BBB opening is safe (according to the assessment of the absence of perivascular edema and apoptosis) and reversible (opening / closing of BBB after 1 h/4 h after exposure to sound, respectively) due to compensatory changes in cerebral blood flow. Thus, sound as a natural factor is a new and promising easily feasible method for the successful delivery of drugs to the brain.

  1. Pardridge W. M. Blood-brain barrier delivery. Drug Discov Today, 2007, vol. 12, pp. 54–61.
  2. Pardridge W. M. Brain drug targeting: the future of brain drug development. Cambridge, Cambridge University Press, 2001. 111 p.
  3. Ghose A. K., Viswanadhan V. N., Wendoloski  J.  J.  A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1.  A qualitative and quantitative characterization of known drug databases. J. Comb Chem., 1999, vol. 1, pp. 55–68.
  4. Hammarlund-Udenaes M., Lange E. de, Thorne R. G. Drug Delivery to the Brain: Physiological Concepts, Methodologies and Approaches. New York, Springer, London, Heiderberg Dordrecht, 2014. 658 p.
  5. Mitragotri S. Devices for overcoming biological barriers: The use of physical forces to disrupt the barriers. Adv. Drug. Deliv. Rev., 2013, vol. 65, pp. 100–103.
  6. Pandey P. K., Sharma A. K., Gupta U. Blood brain bar- rier: An overview on strategies in drug delivery, realistic in vitro modeling and in vivo live tracking. Published  in Tissue Barriers. 2016.DOI:
  7. Hoffmann A. High and low molecular weight fluorescein isothiocyanate (FITC)-dextran to assess blood-brain barrier disruption: technical consideration. Transl Stroke Res., 2011, vol. 2, iss. 1, pp. 106–111.
  8. Wang H.-L., Lai T. W. Optimization of Evans blue quantita- tion in limited rat tissue samples. Sci. Rep., vol. 4, pp. 6588. Published online 2014 Oct 10.DOI:
  9. Boldyrev I. A., Zhai X., Momsen M. M., Brockman H. L., Brown R. E., Molotkovsky J. G. New BODIPY lipid probes for fluorescence studies of membranes. J. Lipid Res., 2007, vol. 48, pp. 1518–1532.
  10. Olson F., Hunt C. A., Szoka F. C., Vail W. J., Papahadjo- poulos D. Preparation of liposomes of defined size distri- bution by extrusion through polycarbonate membranes. Biochim. Biophys. Acta, 1979, vol. 557, pp. 9–23.
  11. Rawson R. A. The binding of T-1824 and structurally related diazo dyes by the plasma proteins. Am. J. Physiol., 1943, vol. 138, pp. 708–717.
  12. Gregersen M. I., Gibson J. J., Stead E. A. Plasma volume determination with dyes: errors in colorimetry; use of the blue dye T-1824. Am. J. Physiol., 1935, vol. 113, pp. 54–55.
  13. Belyaev L., Busto R., Zhao W., Ginsberg M. D. Quan- titative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res., 1996, vol. 739, pp. 88–96.
  14. Chen K. B. Increase in Evans blue dye extravasation into the brain in the late developmental stage. Neuroreport, 2012, vol. 23, pp. 699–701.
  15. Saria A., Lundberg J. M. Evans blue fluorescence: quantitative and morphological evaluation of vascular permeability in animal tissues. J. Neurosci. Methods, 1983, vol. 8, pp. 41–49.
  16. Mora M. Design and characterization of liposomes containing long-chain N-AcylPEs for brain delivery: penetration of liposomes incorporating GM1 into the rat brain. Pharm. Res., 2002, vol. 19, iss. 10, pp. 1430–1438.
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