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New insights into phototherapy of glioblastoma: the meningeal lymphatics and sleep

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Abstract

The meningeal lymphatics (MLVs) play an important role in immunity and maintaining homeostasis of the central nervous system. Sleep is a natural state when lymphatic drainage becomes maximally active and, along with the flow of fluids, toxins and metabolites are removed from the brain. A decrease in function of MLVs is a key mechanism in the development of glioblastoma (GBM), which leads to the accumulation of excess fluid in the brain and an increase in intracranial pressure. Recently, promising methods of transcranial photostimulation (tPBM) of MLVs have been developed. It is interesting to note that tPBM of MLVs during sleep vs. wakefulness stimulates lymphatic drainage of brain tissues much more effectively. It is logical to expect that tPBM of MLVs during sleep will significantly increase the effectiveness of the GBM therapy. This review highlights new trends in the treatment of GBM, including tPBM of MLVs during sleep as a promising strategy in suppression of tumor progression.

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References

  1. S. Grochans, A.M. Cybulska, D. Simińska, J. Korbecki, K. Kojder, D. Chlubek, I. Baranowska-Bosiacka, Epidemiology of glioblastoma multiforme–literature review. Cancers 14, 2412 (2022). https://doi.org/10.3390/cancers14102412

    Article  Google Scholar 

  2. X. Qin, R. Liu, F. Akter, L. Qin, Q. Xie, Y. Li, H. Qiao, W. Zhao, Z. Jian, R. Liu, S. Wu, Peri-tumoral brain edema associated with glioblastoma correlates with tumor recurrence. J. Cancer 12(7), 2073–2082 (2021)

    Article  Google Scholar 

  3. Q. Ma, F. Schlegel, S.B. Bachmann, Lymphatic outflow of cerebrospinal fluid is reduced in glioma. Sci. Rep. 9, 14815 (2019). https://doi.org/10.1038/s41598-019-51373-9

    Article  ADS  Google Scholar 

  4. X. Hu, Q. Deng, L. Ma, Meningeal lymphatic vessels regulate brain tumor drainage and immunity. Cell Res. 30, 229–243 (2020). https://doi.org/10.1038/s41422-020-0287-8

    Article  Google Scholar 

  5. O. Semyachkina-Glushkovskaya, S. Sokolovski, I. Fedosov, A. Shirokov, N. Navolokin, A. Bucharskaya, I. Blokhina, A. Terskov, A. Dubrovski, V. Telnova, A. Tzven, M. Tzoy, A. Evsukova, D. Zhlatogosrkaya, V. Adushkina, A. Dmitrenko, M. Manzhaeva, V. Krupnova, A. Noghero, D. Bragin, O. Bragina, E. Borisova, J. Kurths, E. Rafailov, Transcranial photosensitiser-free laser treatment of glioblastoma in rat brain. Int. J. Mol. Sci. 24, 13696 (2023). https://doi.org/10.3390/ijms241813696

    Article  Google Scholar 

  6. O. Semyachkina-Glushkovskaya, S. Diduk, A. Khorovodov, A. Shirokov, I. Fedosov, A. Dubrovsky, I. Blokhina, A. Terskov, N. Navolokin, A. Evsukova, D. Elovenko, V. Adushkina, J. Kurths, Music improves the therapeutic effects of bevacizumab in rats with glioblastoma: Modulation of drug distribution to the brain. Front. Oncol. 12, 1010188 (2022). https://doi.org/10.3389/fonc.2022.1010188

    Article  Google Scholar 

  7. O. Semyachkina-Glushkovskaya, A. Shirokov, I. Blokhina, V. Telnova, E. Vodovozova, A. Alekseeva, I. Boldyrev, I. Fedosov, A. Dubrovsky, A. Khorovodov, A. Terskov, A. Evsukova, D. Elovenko, V. Adushkina, M. Tzoy, I. Agranovich, J. Kurth, E. Rafailov, Intranasal delivery of liposomes to glioblastoma by photostimulation of the lymphatic system. Pharmaceutics. 15(1), 36 (2023). https://doi.org/10.3390/pharmaceutics15010036

    Article  Google Scholar 

  8. K. Van Raemdonck, S. Umar, K. Palasiewicz, S. Volkov, M.V. Volin, S. Arami, H.J. Chang, B. Zanotti, N. Sweiss, S. Shahrara, CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis. Cell. Mol. Life Sci. 77(7), 1387–1399 (2020). https://doi.org/10.1007/s00018-019-03235-w

    Article  Google Scholar 

  9. E. Song, T. Mao, H. Dong et al., VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature 577, 689–694 (2020). https://doi.org/10.1038/s41586-019-1912-x

    Article  ADS  Google Scholar 

  10. E. Zhinchenko, N. Navolokin, A. Shirokov, B. Khlebcov, A. Dubrovsky, E. Saranceva, A. Abdurashitov, A. Khorovodov, A. Terskov, A. Mamedova, M. Klimova, I. Agranovich, D. Martinov, V. Tuchin, O. Semyachkina-Glushkovskaya, J. Kurts, Pilot study of transcranial photobiomodulation of lymphatic clearance of beta-amyloid from the mouse brain: Breakthrough strategies for nonpharmacologic therapy of Alzheimer’s disease. Biomed. Opt. Exp. 8, 4003–4017 (2019)

    Article  Google Scholar 

  11. O. Semyachkina-Glushkovskaya, T. Penzel, I. Blokhina, A. Khorovodov, I. Fedosov, T. Yu, G. Karandin, A. Evsukova, D. Elovenko, V. Adushkina, A. Shirokov, A. Dubrovskii, A. Terskov, N. Navolokin, M. Tzoy, V. Ageev, I. Agranovich, V. Telnova, A. Tsven, J. Kurths, Night photostimulation of clearance of beta-amyloid from mouse brain: New strategies in preventing Alzheimer’s disease. Cells 10, 3289 (2021)

    Article  Google Scholar 

  12. O. Semyachkina-Glushkovskaya, D. Postnov, A. Lavrova, I. Fedosov, E. Borisova, V. Nikolenko, T. Penzel, J. Kurths, V. Tuchin, Biophotonic strategies of measurement and stimulation of the cranial and the extracranial lymphatic drainage function. IEEE J. Sel. Top. 27, 1–13 (2021)

    Article  Google Scholar 

  13. O. Semyachkina-Glushkovskaya, M. Klimova, T. Iskra, D. Bragin, A. Abdurashitov, A. Dubrovsky, A. Khorovodov, A. Terskov, I. Blokhina, N. Lezhnev, V. Vinnik, I. Agranovich, A. Mamedova, A. Shirokov, N. Navolokin, B. Khlebsov, V. Tuchin, J. Kurths, Transcranial photobiomodulation of clearance of beta-amyloid from the mouse brain: effects on the meningeal lymphatic drainage and blood oxygen saturation of the brain. Adv. Exp. Med. Biol. 1269, 57–61 (2021)

    Article  Google Scholar 

  14. O. Semyachkina-Glushkovskaya, A. Abdurashitov, A. Dubrovsky, M. Klimova, I. Agranovich, A. Terskov, A. Shirokov, V. Vinnik, A. Kuznecova, N. Lezhnev, I. Blokhina, A. Shnitenkova, V. Tuchin, E. Rafailov, J. Kurths, Photobiomodulation of lymphatic drainage and clearance: Perspective strategy for augmentation of meningeal lymphatic functions. Biomed. Opt. Express 11, 725–734 (2020)

    Article  Google Scholar 

  15. E. Zhinchenko, M. Klimova, A. Mamedova, I. Agranovich, I. Blokhina, T. Antonova, A. Terskov, A. Shirokov, N. Navolkin, A. Morgun, E. Osipova, E. Boytsova, T. Yu, D. Zhu, J. Kurths, O. Semyachkina-Glushkovskaya, Photostimulation of extravasation of beta-amyloid through the model of blood-brain barrier. Electronics 9, 1056 (2020)

    Article  Google Scholar 

  16. O. Semyachkina-Glushkovskaya, A. Abdurashitov, M. Klimova, A. Dubrovsky, A. Shirokov, A. Fomin, A. Terskov, I. Agranovich, A. Mamedova, A. Khorovodov, V. Vinnik, I. Blokhina, N. Lezhnev, A.E. Shareef, A. Kuzmina, S. Sokolovski, V. Tuchin, E. Rafailov, J. Kurths, Photostimulation of cerebral and peripheral lymphatic functions. Transl. Biophotonics. 2, e201900036 (2020)

    Article  Google Scholar 

  17. O. Semyachkina-Glushkovskaya, I. Fedosov, A. Shirokov, E. Vodovozova, A. Alekseeva, A. Khorovodov, I. Blokhina, A. Terskov, A. Mamedova, M. Klimova, A. Dubrovsky, V. Ageev, I. Agranovich, V. Vinnik, A. Tsven, S. Sokolovski, E. Rafailov, T. Penzel, J. Kurths, Photomodulation of lymphatic delivery of liposomes to the brain bypassing the blood-brain barrier: new perspectives for glioma therapy. Nanophotonics 12, 3215–3227 (2021)

    Article  Google Scholar 

  18. O. Semyachkina-Glushkovskaya, S. Diduk, A. Eroshova, E. Dosadina, A. Kruglov, A. Khorovodov, A. Shirokov, I. Fedosov, A. Dubrovsky, I. Blokhina, A. Terskov, G. Karandin, A. Evsukova, A. Tsven, V. Telnova, I. Afranovich, S. Sokolovski, E. Rafailov, J. Kurths, Photomodulation of lymphatic delivery of Bevacizumab to the brain: the role of singlet oxygen. Adv. Exp. Med. Biol. 1395, 53–57 (2022)

    Article  Google Scholar 

  19. O. Semyachkina-Glushkovskaya, A. Shirokov, I. Blokhina, V. Telnova, E. Vodovozova, A. Alekseeva, I. Boldyrev, I. Fedosov, A. Dubrovsky, A. Khorovodov, A. Terskov, A. Evsukova, D. Elovenko, V. Adushkina, M. Tzoy, I. Agranovich, J. Kurth, E. Rafailov, Intranasal delivery of liposomes to glioblastoma by photostimulation of the lymphatic system”. Pharmaceutics 15, 36 (2023)

    Article  Google Scholar 

  20. O. Semyachkina-Glushkovskaya, D. Bragin, O. Bragina, S. Socolovski, A. Shirokov, I. Fedosov, V. Ageev, I. Blokhina, A. Dubrovsky, V. Telnova, A. Terskov, A. Khorovodov, D. Elovenko, A. Evsukova, M. Zhoy, I. Agranovich, E. Vodovozova, A. Alekseeva, J. Kurths, E. Rafailov, Low-level laser treatment induces the blood-brain barrier opening and the brain drainage system activation: delivery of liposomes into mouse glioblastoma. Pharmaceutics 15, 567 (2023)

    Article  Google Scholar 

  21. L. Dong-Yu, L. Shao-Jun, Y. Ting-Ting, L. Zhang, S. Si-Lin, D. Bragin, A. Shirokov, N. Navolokin, O. Bragina, Hu. Zheng-Wu, J. Kurths, I. Fedosov, I. Blokhina, A. Dubrovski, A. Khorovodov, A. Terskov, M. Tzoy, O. Semyachkina-Glushkovskaya, Z. Dan, Photostimulation of brain lymphatics in male newborn and adult rodents for therapy of intraventricular hemorrhage. Nature Comm. 14, 6104 (2023). https://doi.org/10.1038/s41467-023-41710-y

    Article  ADS  Google Scholar 

  22. O. Semyachkina-Glushkovskaya, A. Shirokov, I. Blokhina, I. Fedosov, A. Terskov, A. Dubrovsky, M. Tsoy, D. Zlatogosrskaya, V. Adushkina, A. Evsukova, V. Telnova, A. Tzven, V. Krupnova, M. Manzhaeva, A. Dmitrenko, T. Penzel, J. Kurths, Mechanisms of phototherapy of Alzheimer’s disease during sleep and wakefulness: the role of the meningeal lymphatics. Front. Optoelectron. 16, 22 (2023). https://doi.org/10.1007/s12200-023-00080-5

    Article  Google Scholar 

  23. F. Murad, Discovery of some of the biological effects of nitric oxide and its role in cell signaling. Biosci. Rep. 24, 452–474 (2004)

    Article  Google Scholar 

  24. J.C. Drapier, H. Hirling, J. Wietzerbin, P. Kaldy, L.C. Kühn, Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J. 21, 3643–3649 (1993)

    Article  Google Scholar 

  25. M. Lepoivre, F. Fieschi, J. Coves, L. Thelander, M. Fontecave, Inactivation of ribonucleotide reductase by nitric oxide. Biochem. Biophys. Res. Commun. 179, 442–448 (1991)

    Article  Google Scholar 

  26. J.C. Drapier, J.B. Hibbs, Aconitases: a class of metalloproteins highly sensitive to nitric oxide synthesis. Methods Enzymol. 269, 26–36 (1996)

    Article  Google Scholar 

  27. S. Dimmeler, F. Lottspeich, B. Brüne, Nitric oxide causes ADP-ribosylation and inhibition of glyceraldehyde-3-phosphate dehydrogenase. J. Biol. Chem. 267, 16771–16774 (1992)

    Article  Google Scholar 

  28. J.S. Stamler, S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc. Natl. Acad. Sci. 89, 444–448 (1992)

    Article  ADS  Google Scholar 

  29. K. Cosby, Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat. Med. 9, 1498–1505 (2003)

    Article  Google Scholar 

  30. J.H. Crawford, Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 107, 566–574 (2006)

    Article  Google Scholar 

  31. T.S. Isbell, M.T. Gladwin, R.P. Patel, Hemoglobin oxygen fractional saturation regulates nitrite-dependent vasodilation of aortic ring bioassays. Am. J. Physiol. Heart Circ. Physiol. 293, H2565–H2572 (2007)

    Article  Google Scholar 

  32. C. Helms, D.B. Kim-Shapiro, Hemoglobin-mediated nitric oxide signaling. Free Radic. Biol. Med. 61, 464–472 (2013)

    Article  Google Scholar 

  33. Th. Gildner, A. Salinas-Rodríguez, B. Manrique-Espinoza, K. Moreno-Tamayo, P. Kowal, Does poor sleep impair cognition during aging? Longitudinal associations between changes in sleep duration and cognitive performance among older Mexican adults. Arch. Gerontol. Geriatr. 83, 161–168 (2019). https://doi.org/10.1016/j.archger.2019.04.014

    Article  Google Scholar 

  34. J. Lin, F.D. Li, X.G. Chen, F. He, Y.J. Zhai, X.Q. Pan, X.Y. Wang, T. Zhang, M. Yu, Association of postlunch napping duration and night-time sleep duration with cognitive impairment in Chinese elderly: a cross-sectional study. BMJ Open 12, 023188 (2018). https://doi.org/10.1136/bmjopen-2018-023188

    Article  Google Scholar 

  35. S. Da Mesquita, A. Louveau, A. Vaccari, I. Smirnov, R.C. Cornelison, K.M. Kingsmore, C. Contarino, S. Onengut-Gumuscu, E. Farber, D. Raper, K.E. Viar, R.D. Powell, W. Baker, N. Dabhi, R. Bai, R. Cao, S. Hu, S.S. Rich, J.M. Munson, M.B. Lopes, C.C. Overall, S.T. Acton, J. Kipnis, Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560(7717), 185 (2018). https://doi.org/10.1038/s41586-018-0689-7

    Article  ADS  Google Scholar 

  36. L. Xie, H. Kand, Q. Xu, Sleep drives metabolite clearance from the adult brain. Science 342(6156), 373–377 (2013)

    Article  ADS  Google Scholar 

  37. L.M. Hablitz, H.S. Vinitsky, Q. Sun, Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci. Adv. 5(2), eaav5447 (2019)

    Article  ADS  Google Scholar 

  38. N.E. Fultz, G. Bonmassar, K. Setsompop, Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science 366(6465), 628–631 (2019)

    Article  ADS  Google Scholar 

  39. O. Semyachkina-Glushkovskaya, T. Penzel, M. Poluektov, I. Fedosov, M. Tzoy, A. Terskov, I. Blokhina, V. Sidorov, J. Kurths, Phototherapy of Alzheimer’s disease: photostimulation of brain lymphatics during sleep: a systematic review. Int. J. Mol. Sci. 24, 10946 (2023). https://doi.org/10.3390/ijms241310946

    Article  Google Scholar 

  40. O. Semyachkina-Glushkovskaya, I. Fedosov, T. Penzel, D. Li, T. Yu, V. Telnova, E. Kaybeleva, E. Saranceva, A. Terskov, A. Khorovodov, I. Blokhina, J. Kurths, D. Zhu, Brain waste removal system and sleep: Photobiomodulation as an innovative strategy for night therapy of brain diseases. Int. J. Mol. Sci. 24, 3221 (2023). https://doi.org/10.3390/ijms24043221

    Article  Google Scholar 

  41. O. Semyachkina-Glushkovskaya, D. Postnov, T. Penzel, J. Kurths, Sleep as a novel biomarker and a promising therapeutic target for cerebral small vessel disease: a review focusing on Alzheimer’s disease and the blood-brain barrier. Int. J. Mol. Sci. 21, 6293 (2020). https://doi.org/10.3390/ijms21176293

    Article  Google Scholar 

  42. C. Moro, A. Valverde, M. Dole, J. Hoh Kam, C. Hamilton, A. Liebert, B. Bicknell, A.-L. Benabid, P. Magistretti, J. Mitrofanis, The effect of photobiomodulation on the brain during wakefulness and sleep. Front. Neurosci. 16, 942536 (2022)

    Article  Google Scholar 

  43. A. Valverde, C. Hamilton, C. Moro, M. Billeres, P. Magistretti, J. Mitrofanis, Lights at night: Does photobiomodulation improve sleep? Neural Regen. Res. 18, 474–477 (2023)

    Article  Google Scholar 

  44. D. Postnov, O. Semyachkina-Glushkovskaya, E. Litvinenko, J. Kurths, T. Penzel, Mechanisms of activation of brain’s drainage during sleep: the nightlife of astrocytes. Cells 12, 2667 (2023). https://doi.org/10.3390/cells12222667

    Article  Google Scholar 

  45. O. Semyachkina-Glushkovskaya, A. Shirokov, I. Blokhina, I. Fedosov, M. Zoy, A. Dmitrenko, A. Manzhaeva, V. Krupnova, M. Tuzhilkin, A. Terskov, V. Adushkina, D. Zlatogorskaya, V. Telnova, A. Evsukova, I. Ilukov, D. Magkov, D. Tuktarov, A. Dubrovsky, J. Kurths, Phototherapy of glioblastoma during sleep. Pharmaceutics. (2024) (under review)

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Funding

A.S., I.B., A.T. were supported by RSF № 23-25-00296.

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Author notes

  1. Alexander Shirokov, Egor Ilukov, Inna Blokhina, Andrey Terskov, Viktoria Adushkina and Daria Zlatogosrkaya have contributed equally to this work.

Authors and Affiliations

  1. Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences, Prospekt Entuziastov 13, 410049, Saratov, Russia

    Alexander Shirokov

  2. Department of Biology, Saratov State University, Astrakhanskaya 82, 410012, Saratov, Russia

    Alexander Shirokov, Inna Blokhina, Andrey Terskov, Viktoria Adushkina, Daria Zlatogosrkaya & Valeria Telnova

  3. Institute of Physics, Saratov State University, Astrakhanskaya Str. 83, 410012, Saratov, Russia

    Egor Ilukov

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Contributions

AS initiated and supervised this review article; AS wrote Abstract and Conclusions; IB, VA, DZ, VT prepared the section “Lymphatic drainage of brain tissues is reduced in GBM”; AS, EI, and AT prepared the section “Photobiomodulation of the MLV functions as a new promising strategy in reducing the GBM growth”. All authors were also involved in the editing of the manuscript; AS prepared the figures. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Alexander Shirokov.

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Shirokov, A., Ilukov, E., Blokhina, I. et al. New insights into phototherapy of glioblastoma: the meningeal lymphatics and sleep. Eur. Phys. J. Spec. Top. 233, 691–697 (2024). https://doi.org/10.1140/epjs/s11734-023-01083-1

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