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1. Music improves the therapeutic effects of bevacizumab in rats with glioblastoma: Modulation of drug distribution to the brain

Author

Semyachkina-Glushkovskaya, Oxana, Diduk, Sergey, Anna, Eroshova, Elina, Dosadina, Artem, Kruglov, Khorovodov, Alexander, Shirokov, Alexander, Fedosov, Ivan, Dubrovsky, Alexander, Blokhina, Inna, Terskov, Andrey, Navolokin, Nikita, Evsukova, Arina, Elovenko, Daria, Adushkina, Viktoria, and Kurths, Jürgen

Subjects
brain drug delivery, Cancer Research, Oncology, music, ddc:610, blood-brain barrier, bevacizumab, 610 Medizin und Gesundheit, rat glioblastoma
Abstract

BackgroundThe development of new methods for modulation of drug distribution across to the brain is a crucial step in the effective therapies for glioblastoma (GBM). In our previous work, we discovered the phenomenon of music-induced opening of the blood-brain barrier (OBBB) in healthy rodents. In this pilot study on rats, we clearly demonstrate that music-induced BBB opening improves the therapeutic effects of bevacizumab (BZM) in rats with GBM via increasing BZM distribution to the brain along the cerebral vessels.MethodsThe experiments were performed on Wistar male rats (200–250 g, n=161) using transfected C6-TagRFP cell line and the loud rock music for OBBB. The OBBB was assessed by spectrofluorometric assay of Evans Blue (EB) extravasation and confocal imaging of fluorescent BZM (fBZM) delivery into the brain. Additionally, distribution of fBZM and Omniscan in the brain was studied using fluorescent and magnetic resonance imaging (MRI), respectively. To analyze the therapeutic effects of BZM on the GBM growth in rats without and with OBBB, the GBM volume (MRI scans), as well as immunohistochemistry assay of proliferation (Ki67 marker) and apoptosis (Bax marker) in the GBM cells were studied. The Mann–Whitney–Wilcoxon test was used for all analysis, the significance level was p < 0.05, n=7 in each group.ResultsOur finding clearly demonstrates that music-induced OBBB increases the delivery of EB into the brain tissues and the extravasation of BZM into the brain around the cerebral vessels of rats with GBM. Music significantly increases distribution of tracers (fBZM and Omniscan) in the rat brain through the pathways of brain drainage system (perivascular and lymphatic), which are an important route of drug delivery into the brain. The music-induced OBBB improves the suppressive effects of BZM on the GBM volume and the cellular mechanisms of tumor progression that was accompanied by higher survival among rats in the GBM+BZM+Music group vs. other groups.ConclusionWe hypothesized that music improves the therapeutic effects of BZM via OBBB in the normal cerebral vessels and lymphatic drainage of the brain tissues. This contributes better distribution of BZM in the brain fluids and among the normal cerebral vessels, which are used by GBM for invasion and co-opt existing vessels as a satellite tumor form. These results open the new perspectives for an improvement of therapeutic effects of BZM via the music-induced OBBB for BZM in the normal cerebral vessels, which are used by GBM for migration and progression.

Published
2022
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2. Abstract WP414: Transcranial Photobiomodulation of Clearance of Blood Products From the Neonatal Brain via the Meningeal Lymphatics

Author

Oxana Semyachkina-Glushkovskaya, Maria Klimova, Kurths Juergen, Navolokin Nikita, and Alexander Shirokov

Subjects
Advanced and Specialized Nursing, Pathology, medicine.medical_specialty, Lymphatic system, Meningeal lymphatic vessels, business.industry, Deep cervical lymph nodes, Hemosiderin, Neonatal brain, Medicine, Neurology (clinical), Cardiology and Cardiovascular Medicine, business
Abstract

In human data we observed the presence of products of degraded blood (the iron/hemosiderin) in the meningeal lymphatic vessels (MLVs) and in the deep cervical lymph node (dcLN) in newborns who died after intracranial hemorrhages. Here we demonstrate novel data related to transcranial photobiomodulation (tPBM) of clearance of blood products (the iron/hemosiderin) from the brain via MLVs in newborn rats after stress-induced intracranial hemorrhages (SIH). Experiments were carried out in 73 newborn rats (5 g) with SIH. All procedures were performed in accordance with the “Position of the American Heart Association on Research Animal Use” (Circulation 1985; 71:849A). The new generation laser 1268 nm (30 nm, 7 min) was used for tPBM of lymphatic clearance of blood products that was analyzed in vivo (two-photon, fluorescent, optical coherent tomography imaging) and ex vivo (immunohistochemical, confocal data) using markers of cerebral and lymphatic endothelium (CD31, LYVE-1/LYVE-1 conjugated with Alexa 488 and Prox-1). The results clearly demonstrated that 30 min after SIH the iron/hemosiderin (detected by atomic absorption spectroscopy and histological method) accumulated in the dcLN and observed in the MLVs. The tPBM caused stimulation of lymphatic drainage function that was accompanied by decrease in the iron/hemosiderin level in the brain tissues with an appropriate increase of their level in the dcLN. The tPBM (one time a day) during one week contributed a better recovery after SIH vs. the control group (without tPBM) that was confirmed by analysis of inflammatory factors (C-reactive protein, IL-6 and lipoprotein-associated phospholipase A2, immunoassay analysis), macrophages infiltration (confocal imaging), edema, necrotic and ischemic events (histological data). In sum, our results suggest that tPBM by stimulation of endogenous processes of cerebral lymphatic drainage and clearing function might be a novel non-invasive approach for brain recovery after neonatal intracranial hemorrhages. The research was supported by grant of Russian Science Foundation No 18-75-10033.

Published
2020
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3. Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

Author

Galina P. Martynova, Anna Gerhartl, Arkadiusz Liskiewicz, Candan Gürses, David Bueno, Jens Pahnke, Mie Kristensen, Andrzej Małecki, Claus U. Surma, Edward A. Neuwelt, Lars Bo Nielsen, Sándor Valkai, László Puskás, Gerald A. Grant, Petra Majerova, Fruzsina R. Walter, Wendy W.J. Unger, Sercin Karahuseyinoglu, Matheus Uba Chupel, Inez Fręśko, Semyachkina-Glushkovskaya Oxana, Marta Martinez-Morga, Shinsuke Nakagawa, Marian M. Humphries, Niamh Doyle, Shareef Ali Esmat, A. Cubukova, Sabela Rodríguez-Lorenzo, Pietra Candela, James F. Meaney, Dóra V Lipka, Ruud D Fontijn, Malinovskaya Nataliya, Salmina Alla, H. Zieliński, Chih-Chieh Tsao, Svetlana Drndarski, Raquel Garcia-Lopez, Alon Friedman, Pavlov Valery, David A. Antonetti, Kinga G. Blecharz, Nobutaka Horie, Anna Huber, Ana Raquel Santa Maria, Mária Mészáros, Marco Metzger, Sonja Thom, Ronel Veksler, Vilmos Tubak, Emmanuel Sevin, Magdalena Zielińska, Holger Gerhardt, Samar Osmen, Bucharskaya Alla, Nadir Arican, Zsolt Török, Bragin Denis, David J. Begley, Szilvia Veszelka, Marta Kowalewska, Torben Moos, Takayuki Matsuo, Cathrin J. Czupalla, Vladimir Soukhoroukov, Alena Michalicova, Krzysztof Milewski, Chris H. Greene, Jianming Xiang, Alla B. Salmina, Mike Veenstra, Andrea Fuso, Lester R. Drewes, Peter Galajda, Udi Vazana, Christina Dilling, Gizem Nur Sahin, Guohua Xi, N. Joan Abbott, Conor Delaney, Natalie Hudson, Malgorzata Burek, Lisa Juul Routhe, Sabrina Engelhardt, Janina Skipor, Enming Joe Su, Simon J. O'Carroll, István A. Krizbai, Gergő Porkoláb, Tsuyoshi Izumo, Romain Versele, Poyraz Düzgün, Kenta Ujifuku, Mariangela Corsi, Dan Z. Milikovsky, Ana-Maria Pilbat, Muge Atis, Nurcan Orhan, Agata Krawczynska, Mária A. Deli, Dmitri Sisario, Isabelle Gruber, Andrej Kovac, Manuel Sarmiento Soto, Anna Schönegger, E. Scott Graham, Marta Skowrońska, Yana V. Gorina, Hans Christian Cederberg Helms, Minseon Park, András Kincses, Niloufar Zarghami, Judit Váradi, Michael G. Molloy, Michal Toborek, Anne Iltzsche, Anika M.S. Hartz, Sarah L. Doyle, Yoichi Morofuji, Zsolt Bozsó, Joan W. Berman, Morgun Andrey, Elizaveta B. Boytsova, Nicole Kachappilly, Susan Morgello, Ursula Wyneken, Gekalyuk Artem, Sheng-Fu Huang, Miklós Vecsernyés, David Male, John Kealy, Khorovodov Alexander, Victor Castro, Shushunova Anastasia, Bodrova Madina, Jaroslav Galba, Luciele Guerra Minuzzi, Karl-Heinz Plate, Helle S. Waagepetersen, Nicola R. Sibson, Janina Skipor-Lahuta, Khilazheva Elena, Ferenc Fenyvesi, Alwin Kamermans, Marta Nowacka-Chmielewska, Fang Niu, Rouhollah Khodadust, Josephin Wagner, Loránd Kiss, Lyna Solomon-Kamintsky, Peter Vajkoczy, Daniel A. Lawrence, Alexander Reitner, Niall Pender, Lucia Celkova, Sidar Aydin, Mikio Furuse, Kavi Devraj, Christina Simoglou Karali, Andrey V. Morgun, Aleksandra Szczepkowska, Guy Bar-Klein, Krzysztof Kucharz, Ádám Nyúl-Tóth, Lívia Fülöp, Martin Lauritzen, Yvonne Couch, Rémy Bruggmann, Mihály Kozma, Marta Obara-Michlewska, Julia Baumann, Franco Laccone, Hannes Steinkellner, A. Appelt-Menzel, Catherine E. Angel, Colin P. Doherty, Dan T Kho, Attila Farkas, Kathrin Hahn, Omolara Ogunshola, Arzu Temizyurek, Roman Fischer, Melissa A. Lopes-Pinheiro, Armelle Klopstein, Vodovozova Elena, Zsolt Radak, Sylvaine Guérit, Mehmet Kaya, Dror Rosenbach, Nikolay Kutuzov, M. Surma, Carsten Uhd Nielsen, Takeo Anda, Rita Businaro, Navolokin Nikita, Jennifer Pereira, András Dér, Alekseeva Anna, Kurths Jürgen, Richard F. Keep, Dionna W. Williams, Stefan Liebner, Nikolett Lénárt, Melinda E. Tóth, Edith Filaire, Boytsova Elizaveta, Elena D. Khilazheva, Ana Rita Bras, Péter Nagyőszi, Alexa Fries, Edyta Skonieczna, Bulent Ahishali, Daniel C. Anthony, Mutlu Küçük, Lydia Gabbert, Shirokov Alexander, Canan Yilmaz, Lars Winkler, A. Bach, Ulanova Mariya, Eoin Kelly, Rosiris Leon Rivera, Luca Marchetti, Hong Ye, Tuchin Artem, Jamie Lim, Helga E. de Vries, Salvador Martinez, Ágnes Kittel, Ágnes Zvara, Imola Wilhelm, Steffen E. Storck, Ana Pombero, Matthew Campbell, Luis Federico Bátiz, Sandra Mihaljevic, Laurence Fenart, Jordi Garcia-Fernàndez, Ignacio A. Romero, Birger Brodin, Daniela Kasprowska-Liśkiewicz, Brigitta Dukay, David M. F. Francisco, Karl Schoknecht, Ana C. Calpena, Neli Bounzina, Eugene Wallace, Ofer Prager, Jack van Horssen, Abdurashitov Arkady, Kinga Molnár, Michael Farrell, Miklós Sántha, Shilpa Buch, Marta Espina, Salmin Vladimir, Ya Hua, Serkan Emik, Ulf C. Schneider, Elena A. Pozhilenkova, Omolara O. Ogunshola, Eoin O’Keefe, Judit P. Vigh, David Francisco, Gijs Kooij, Takashi Fujimoto, Britta Engelhardt, Daisuke Watanabe, Z. Giżejewski, Alexandra Bocsik, Csilla Fazakas, Zsófia Hoyk, Marcelle Silva de Abreu, Stephanie Hughes, Vinton W.T. Cheng, Rebecca Johnson, Andrzej P. Herman, János Haskó, András Harazin, E. Fidan, Richard Kovács, Yang Yirong, Cherubino Di Lorenzo, Ana Maria Teixeira, Mette Mathiesen Janiurek, Krisztina Nagy, Umut Deniz Ceylan, Winfried Neuhaus, Uğur Akcan, Jadranka Macas, Kristian Strømgaard, Sagatova Artem, Christina Christoffersen, Ralph M. Garruto, Marta Przybyła, Maria Luisa García, Fabien Gosselet, Ruth Lyck, and Michal Novak

Subjects
0301 basic medicine, business.industry, General Medicine, Meeting Abstracts, lcsh:RC346-429, 03 medical and health sciences, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, Developmental Neuroscience, Neurology, Medicine, Signal transduction, business, Neuroscience, lcsh:Neurology. Diseases of the nervous system, 030217 neurology & neurosurgery
Published
2017
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