Browsing by Author "Semyachkina-Glushkovskaya, Oxana"
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- ItemApplication of optical coherence tomography for in vivo monitoring of the meningeal lymphatic vessels during opening of blood–brain barrier: mechanisms of brain clearing(Bellingham, Wash. : SPIE, 2017) Semyachkina-Glushkovskaya, Oxana; Abdurashitov, Arkady; Dubrovsky, Alexander; Bragin, Denis; Bragina, Olga; Shushunova, Natalia; Maslyakova, Galina; Navolokin, Nikita; Bucharskaya, Alla; Tuchind, Valery; Kurths, Jürgen; Shirokov, AlexanderThe meningeal lymphatic vessels were discovered 2 years ago as the drainage system involved in the mechanisms underlying the clearance of waste products from the brain. The blood–brain barrier (BBB) is a gatekeeper that strongly controls the movement of different molecules from the blood into the brain. We know the scenarios during the opening of the BBB, but there is extremely limited information on how the brain clears the substances that cross the BBB. Here, using the model of sound-induced opening of the BBB, we clearly show how the brain clears dextran after it crosses the BBB via the meningeal lymphatic vessels. We first demonstrate successful application of optical coherence tomography (OCT) for imaging of the lymphatic vessels in the meninges after opening of the BBB, which might be a new useful strategy for noninvasive analysis of lymphatic drainage in daily clinical practice. Also, we give information about the depth and size of the meningeal lymphatic vessels in mice. These new fundamental data with the applied focus on the OCT shed light on the mechanisms of brain clearance and the role of lymphatic drainage in these processes that could serve as an informative platform for a development of therapy and diagnostics of diseases associated with injuries of the BBB such as stroke, brain trauma, glioma, depression, or Alzheimer disease.
- ItemBlood–Brain Barrier, Lymphatic Clearance, and Recovery: Ariadne’s Thread in Labyrinths of Hypotheses(Basel : Molecular Diversity Preservation International, 2018) Semyachkina-Glushkovskaya, Oxana; Postnov, Dmitry; Kurths, JürgenThe peripheral lymphatic system plays a crucial role in the recovery mechanisms after many pathological changes, such as infection, trauma, vascular, or metabolic diseases. The lymphatic clearance of different tissues from waste products, viruses, bacteria, and toxic proteins significantly contributes to the correspondent recovery processes. However, understanding of the cerebral lymphatic functions is a challenging problem. The exploration of mechanisms of lymphatic communication with brain fluids as well as the role of the lymphatic system in brain drainage, clearance, and recovery is still in its infancy. Here we review novel concepts on the anatomy and physiology of the lymphatics in the brain, which warrant a substantial revision of our knowledge about the role of lymphatics in the rehabilitation of the brain functions after neural pathologies. We discuss a new vision on the connective bridge between the opening of a blood–brain barrier and activation of the meningeal lymphatic clearance. The ability to stimulate the lymph flow in the brain, is likely to play an important role in developing future innovative strategies in neurorehabilitation therapy.
- ItemBrain Mechanisms of COVID-19-Sleep Disorders(Basel : Molecular Diversity Preservation International (MDPI), 2021) Semyachkina-Glushkovskaya, Oxana; Mamedova, Aysel; Vinnik, Valeria; Klimova, Maria; Saranceva, Elena; Ageev, Vasily; Yu, Tingting; Zhu, Dan; Penzel, Thomas; Kurths, Jürgen2020 and 2021 have been unprecedented years due to the rapid spread of the modified severe acute respiratory syndrome coronavirus around the world. The coronavirus disease 2019 (COVID-19) causes atypical infiltrated pneumonia with many neurological symptoms, and major sleep changes. The exposure of people to stress, such as social confinement and changes in daily routines, is accompanied by various sleep disturbances, known as ‘coronasomnia’ phenomenon. Sleep disorders induce neuroinflammation, which promotes the blood–brain barrier (BBB) disruption and entry of antigens and inflammatory factors into the brain. Here, we review findings and trends in sleep research in 2020–2021, demonstrating how COVID-19 and sleep disorders can induce BBB leakage via neuroinflammation, which might contribute to the ‘coronasomnia’ phenomenon. The new studies suggest that the control of sleep hygiene and quality should be incorporated into the rehabilitation of COVID-19 patients. We also discuss perspective strategies for the prevention of COVID-19-related BBB disorders. We demonstrate that sleep might be a novel biomarker of BBB leakage, and the analysis of sleep EEG patterns can be a breakthrough non-invasive technology for diagnosis of the COVID-19-caused BBB disruption.
- ItemIntranasal Delivery of Liposomes to Glioblastoma by Photostimulation of the Lymphatic System(Basel : MDPI, 2022) Semyachkina-Glushkovskaya, Oxana; Shirokov, Alexander; Blokhina, Inna; Telnova, Valeria; Vodovozova, Elena; Alekseeva, Anna; Boldyrev, Ivan; Fedosov, Ivan; Dubrovsky, Alexander; Khorovodov, Alexandr; Terskov, Andrey; Evsukova, Arina; Elovenko, Daria; Adushkina, Viktoria; Tzoy, Maria; Agranovich, Ilana; Kurths, Jürgen; Rafailov, EdikThe blood–brain barrier (BBB) limits the delivery of majority of cancer drugs and thereby complicates brain tumor treatment. The nasal-brain-lymphatic system is discussed as a pathway for brain drug delivery overcoming the BBB. However, in most cases, this method is not sufficient to achieve a therapeutic effect due to brain drug delivery in a short distance. Therefore, it is necessary to develop technologies to overcome the obstacles facing nose-to-brain delivery of promising pharmaceuticals. In this study, we clearly demonstrate intranasal delivery of liposomes to the mouse brain reaching glioblastoma (GBM). In the experiments with ablation of the meningeal lymphatic network, we report an important role of meningeal pathway for intranasal delivery of liposomes to the brain. Our data revealed that GBM is characterized by a dramatic reduction of intranasal delivery of liposomes to the brain that was significantly improved by near-infrared (1267 nm) photostimulation of the lymphatic vessels in the area of the cribriform plate and the meninges. These results open new perspectives for non-invasive improvement of efficiency of intranasal delivery of cancer drugs to the brain tissues using nanocarriers and near-infrared laser-based therapeutic devices, which are commercially available and widely used in clinical practice.
- ItemModified wavelet analysis of ECoG-pattern as promising tool for detection of the blood–brain barrier leakage([London] : Macmillan Publishers Limited, part of Springer Nature, 2021) Runnova, Anastasiya; Zhuravlev, Maksim; Ukolov, Rodion; Blokhina, Inna; Dubrovski, Alexander; Lezhnev, Nikita; Sitnikova, Evgeniya; Saranceva, Elena; Kiselev, Anton; Karavaev, Anatoly; Selskii, Anton; Semyachkina-Glushkovskaya, Oxana; Penzel, Thomas; Kurths, JurgenA new approach for detection oscillatory patterns and estimation of their dynamics based by a modified CWT skeleton method is presented. The method opens up additional perspectives for the analysis of subtle changes in the oscillatory activity of complex nonstationary signals. The method was applied to analyze unique experimental signals obtained in usual conditions and after the non-invasive increase in the blood–brain barrier (BBB) permeability in 10 male Wistar rats. The results of the wavelet-analysis of electrocorticography (ECoG) recorded in a normal physiological state and after an increase in the BBB permeability of animals demonstrate significant changes between these states during wakefulness of animals and an essential smoothing of these differences during sleep. Sleep is closely related to the processes of observed changes in the BBB permeability.
- ItemMusic improves the therapeutic effects of bevacizumab in rats with glioblastoma: Modulation of drug distribution to the brain(Lausanne : Frontiers Media, 2022) 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; Kurths, JürgenBackground: The 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. Methods: The 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. Results: Our 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. Conclusion: We 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.
- ItemPhotobiomodulation of lymphatic drainage and clearance: Perspective strategy for augmentation of meningeal lymphatic functions(Washington, DC : Optica, 2020) Semyachkina-Glushkovskaya, Oxana; Abdurashitov, Arkady; Dubrovsky, Alexander; Klimova, Maria; Agranovich, Ilana; Terskov, Andrey; Shirokov, Alexander; Vinnik, Valeria; Kuzmina, Anna; Lezhnev, Nikita; Blokhina, Inna; Shnitenkova, Anastassia; Tuchin, Valery; Rafailov, Edik; Kurths, JurgenThere is a hypothesis that augmentation of the drainage and clearing function of the meningeal lymphatic vessels (MLVs) might be a promising therapeutic target for preventing neurological diseases. Here we investigate mechanisms of photobiomodulation (PBM, 1267 nm) of lymphatic drainage and clearance. Our results obtained at optical coherence tomography (OCT) give strong evidence that low PBM doses (5 and 10 J/cm2) stimulate drainage function of the lymphatic vessels via vasodilation (OCT data on the mesenteric lymphatics) and stimulation of lymphatic clearance (OCT data on clearance of gold nanorods from the brain) that was supported by confocal imaging of clearance of FITC-dextran from the cortex via MLVs. We assume that PBM-mediated relaxation of the lymphatic vessels can be possible mechanisms underlying increasing the permeability of the lymphatic endothelium that allows molecules transported by the lymphatic vessels and explain PBM stimulation of lymphatic drainage and clearance. These findings open new strategies for the stimulation of MLVs functions and non-pharmacological therapy of brain diseases.
- ItemPhotodynamic opening of the blood-brain barrier using different photosensitizers in mice(Basel : MDPI, 2019) Semyachkina-Glushkovskaya, Oxana; Borisova, Ekaterina; Mantareva, Vanya; Angelov, Ivan; Eneva, Ivelina; Terskov, Andrey; Mamedova, Aysel; Shirokov, Alexander; Khorovodov, Alexander; Klimova, Maria; Agranovich, Ilana; Blokhina, Inna; Lezhnev, Nikita; Kurths, JurgenIn a series of previous studies, we demonstrated that the photodynamic therapy (PDT), as a widely used tool for treatment of glioblastoma multiforme (GBM), also site-specifically opens the blood-brain barrier (BBB) in PDT-dose and age-related manner via reversible disorganization of the tight junction machinery. To develop the effective protocol of PDT-opening of the BBB, here we answer the question of what kind of photosensitizer (PS) is the most effective for the BBB opening. We studied the PDT-opening of the BBB in healthy mice using commercial photosensitizers (PSs) such as 5-aminolevulenic acid (5-ALA), aluminum phthalocyanine disulfonate (AlPcS), zinc phthalocyanine (ZnPc) and new synthetized PSs such as galactose functionalized ZnPc (GalZnPc). The spectrofluorimetric assay of Evans Blue albumin complex (EBAC) leakage and 3-D confocal imaging of FITC-dextran 70 kDa (FITCD) extravasation clearly shows a revisable and dose depended PDT-opening of the BBB toEBACand FITCD associated with a decrease in presence of tight junction (TJ) in the vascular endothelium. The PDT effects on the BBB permeability, TJ expression and the fluorescent signal from the brain tissues are more pronounced in PDT-GalZnPc vs. PDT-5-ALA/AlPcS/ZnPc. These pre-clinical data are the first important informative platform for an optimization of the PDT protocol in the light of new knowledge about PDT-opening of the BBB for drug brain delivery and for the therapy of brain diseases. © 2019 by the authors.
- ItemPhotodynamic Opening of the Blood–Brain Barrier and the Meningeal Lymphatic System: The New Niche in Immunotherapy for Brain Tumors(Basel : MDPI, 2022) Semyachkina-Glushkovskaya, Oxana; Terskov, Andrey; Khorovodov, Alexander; Telnova, Valeria; Blokhina, Inna; Saranceva, Elena; Kurths, JürgenPhotodynamic therapy (PDT) is a promising add-on therapy to the current standard of care for patients with glioblastoma (GBM). The traditional explanation of the anti-cancer PDT effects involves the PDT-induced generation of a singlet oxygen in the GBM cells, which causes tumor cell death and microvasculature collapse. Recently, new vascular mechanisms of PDT associated with opening of the blood–brain barrier (OBBB) and the activation of functions of the meningeal lymphatic vessels have been discovered. In this review, we highlight the emerging trends and future promises of immunotherapy for brain tumors and discuss PDT-OBBB as a new niche and an important informative platform for the development of innovative pharmacological strategies for the modulation of brain tumor immunity and the improvement of immunotherapy for GBM.
- ItemPhotomodulation of lymphatic delivery of liposomes to the brain bypassing the blood-brain barrier: new perspectives for glioma therapy(Berlin : de Gruyter, 2021) Semyachkina-Glushkovskaya, Oxana; Fedosov, Ivan; Shirokov, Alexander; Vodovozova, Elena; Alekseeva, Anna; Khorovodov, Alexandr; Blokhina, Inna; Terskov, Andrey; Mamedova, Aysel; Klimova, Maria; Dubrovsky, Alexander; Ageev, Vasily; Agranovich, Ilana; Vinnik, Valeria; Tsven, Anna; Sokolovski, Sergey; Rafailov, Edik; Penzel, Thomas; Kurths, JürgenThe blood-brain barrier (BBB) has a significant contribution to the protection of the central nervous system (CNS). However, it also limits the brain drug delivery and thereby complicates the treatment of CNS diseases. The development of safe methods for an effective delivery of medications and nanocarriers to the brain can be a revolutionary step in the overcoming this limitation. Here, we report the unique properties of the lymphatic system to deliver tracers and liposomes to the brain meninges, brain tissues, and glioma in rats. Using a quantum-dot-based 1267 nm laser (for photosensitizer-free generation of singlet oxygen), we clearly demonstrate photostimulation of lymphatic delivery of liposomes to glioma as well as lymphatic clearance of liposomes from the brain. These pilot findings open promising perspectives for photomodulation of lymphatic delivery of drugs and nanocarriers to the brain pathology bypassing the BBB. The lymphatic “smart” delivery of liposomes with antitumor drugs in the new brain tumor branches might be a breakthrough strategy for the therapy of gliomas.
- ItemPhotostimulation of extravasation of beta-amyloid through the model of blood-brain barrier(Basel : MDPI AG, 2020) Zinchenko, Ekaterina; Klimova, Maria; Mamedova, Aysel; Agranovich, Ilana; Blokhina, Inna; Antonova, Tatiana; Terskov, Andrey; Shirokov, Alexander; Navolokin, Nikita; Morgun, Andrey; Osipova, Elena; Boytsova, Elizaveta; Yu, Tingting; Zhu, Dan; Kurths, Juergen; Semyachkina-Glushkovskaya, OxanaAlzheimer’s disease (AD) is an incurable pathology associated with progressive decline in memory and cognition. Phototherapy might be a new promising and alternative strategy for the effective treatment of AD, and has been actively discussed over two decades. However, the mechanisms of therapeutic photostimulation (PS) effects on subjects with AD remain poorly understood. The goal of this study was to determine the mechanisms of therapeutic PS effects in beta-amyloid (Aβ)-injected mice. The neurological severity score and the new object recognition tests demonstrate that PS 9 J/cm2 attenuates the memory and neurological deficit in mice with AD. The immunohistochemical assay revealed a decrease in the level of Aβ in the brain and an increase of Aβ in the deep cervical lymph nodes obtained from mice with AD after PS. Using the in vitro model of the blood-brain barrier (BBB), we show a PS-mediated decrease in transendothelial resistance and in the expression of tight junction proteins as well an increase in the BBB permeability to Aβ. These findings suggest that a PS-mediated BBB opening and the activation of the lymphatic clearance of Aβ from the brain might be a crucial mechanism underlying therapeutic effects of PS in mice with AD. These pioneering data open new strategies in the development of non-pharmacological methods for therapy of AD and contribute to a better understanding of the PS effects on the central nervous system. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemSleep 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(Basel : Molecular Diversity Preservation International, 2020) Semyachkina-Glushkovskaya, Oxana; Postnov, Dmitry; Penzel, Thomas; Kurths, JürgenCerebral small vessel disease (CSVD) is a leading cause of cognitive decline in elderly people and development of Alzheimer’s disease (AD). Blood–brain barrier (BBB) leakage is a key pathophysiological mechanism of amyloidal CSVD. Sleep plays a crucial role in keeping health of the central nervous system and in resistance to CSVD. The deficit of sleep contributes to accumulation of metabolites and toxins such as beta-amyloid in the brain and can lead to BBB disruption. Currently, sleep is considered as an important informative platform for diagnosis and therapy of AD. However, there are no effective methods for extracting of diagnostic information from sleep characteristics. In this review, we show strong evidence that slow wave activity (SWA) (0–0.5 Hz) during deep sleep reflects glymphatic pathology, the BBB leakage and memory deficit in AD. We also discuss that diagnostic and therapeutic targeting of SWA in AD might lead to be a novel era in effective therapy of AD. Moreover, we demonstrate that SWA can be pioneering non-invasive and bed–side technology for express diagnosis of the BBB permeability. Finally, we review the novel data about the methods of detection and enhancement of SWA that can be biomarker and a promising therapy of amyloidal CSVD and CSVD associated with the BBB disorders. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemThe stress and vascular catastrophes in newborn rats: Mechanisms preceding and accompanying the brain hemorrhages(Lausanne : Frontiers Media, 2016) Semyachkina-Glushkovskaya, Oxana; Borisova, Ekaterina; Abakumov, Maxim; Gorin, Dmitry; Avramov, Latchezar; Fedosov, Ivan; Namykin, Anton; Abdurashitov, Arkady; Serov, Alexander; Pavlov, Alexey; Zinchenko, Ekaterina; Lychagov, Vlad; Navolokin, Nikita; Shirokov, Alexander; Maslyakova, Galina; Zhu, Dan; Luo, Qingming; Chekhonin, Vladimir; Tuchin, Valery; Kurths, JürgenIn this study, we analyzed the time-depended scenario of stress response cascade preceding and accompanying brain hemorrhages in newborn rats using an interdisciplinary approach based on: a morphological analysis of brain tissues, coherent-domain optical technologies for visualization of the cerebral blood flow, monitoring of the cerebral oxygenation and the deformability of red blood cells (RBCs). Using a model of stress-induced brain hemorrhages (sound stress, 120 dB, 370 Hz), we studied changes in neonatal brain 2, 4, 6, 8 h after stress (the pre-hemorrhage, latent period) and 24 h after stress (the post-hemorrhage period). We found that latent period of brain hemorrhages is accompanied by gradual pathological changes in systemic, metabolic, and cellular levels of stress. The incidence of brain hemorrhages is characterized by a progression of these changes and the irreversible cell death in the brain areas involved in higher mental functions. These processes are realized via a time-depended reduction of cerebral venous blood flow and oxygenation that was accompanied by an increase in RBCs deformability. The significant depletion of the molecular layer of the prefrontal cortex and the pyramidal neurons, which are crucial for associative learning and attention, is developed as a consequence of homeostasis imbalance. Thus, stress-induced processes preceding and accompanying brain hemorrhages in neonatal period contribute to serious injuries of the brain blood circulation, cerebral metabolic activity and structural elements of cognitive function. These results are an informative platform for further studies of mechanisms underlying stress-induced brain hemorrhages during the first days of life that will improve the future generation's health.