Alexander Dubrovsky

Background and Objectives: The molecular transport in the brain tissue is yet to be fully studied and presents great interest to the researchers in the fields of biophysics and biomedicine. Diffusion and molecular transport processes in brain tissues are defined by the properties of the intercellular space of the central nervous system. The object of this work is to develop a method for ex vivo quantitative measurements of diffusion in the brain tissues of laboratory mice. Materials and Methods: Multiphotonmicroscopy-based fluorescence recovery after photobleaching was applied in the analysis of fluorescent dye molecular mobility dynamics in mouse brain tissue. Results: The results of the fluorescence recovery dynamics analysis in an ex vivo slab of the mouse brain have been used for molecular diffusion mapping in a layer of brain tissues of a laboratory mouse. Diffusion coefficients in several sections of the layer of brain tissues have been calculated based on a simplified diffusion model and fluorescence recovery after photobleaching data. Conclusion: Fluorescence recovery after photobleaching with multiphoton microscopy are applicable in the creation of the molecular diffusion map in the brain tissue of a laboratory mouse.

Amyloid beta (Aβ) is a neuronal metabolic product that plays an important role in maintaining brain homeostasis. Normally, intensive brain Aβ formation is accompanied by its effective lymphatic removal. However, the excessive accumulation of brain Aβ is observed with age and during the development of Alzheimer’s disease (AD) leading to cognitive impairment and memory deficits. There is emerging evidence that plasmalogens (Pls), as one of the key brain lipids, may be beneficial for AD and cognitive aging. Here, we studied the effects of Pls on cognitive functions and the lymphatic clearance of Aβ from the brain of AD mice and mice of different ages. The results showed that Pls effectively reduce brain Aβ levels and facilitate learning in aged but not old mice. In AD mice, Pls improve the lymphatic clearance of Aβ that is accompanied by an increase in general motor activity and an improvement of the emotional status and learning ability. Thus, these findings suggest that Pls could be a promising candidate for the alternative or concomitant therapy of AD and age-related brain diseases to enhance the lymphatic clearance of Aβ from the brain and cognitive functions.

There is an association between sleep quality and glioma-specific outcomes, including survival. The critical role of sleep in survival among subjects with glioma may be due to sleep-induced activation of brain drainage (BD), that is dramatically suppressed in subjects with glioma. Emerging evidence demonstrates that photobiomodulation (PBM) is an effective technology for both the stimulation of BD and as an add-on therapy for glioma. Emerging evidence suggests that PBM during sleep stimulates BD more strongly than when awake. In this study on male Wistar rats, we clearly demonstrate that the PBM course during sleep vs. when awake more effectively suppresses glioma growth and increases survival compared with the control. The study of the mechanisms of this phenomenon revealed stronger effects of the PBM course in sleeping vs. awake rats on the stimulation of BD and an immune response against glioma, including an increase in the number of CD8+ in glioma cells, activation of apoptosis, and blockage of the proliferation of glioma cells. Our new technology for sleep-phototherapy opens a new strategy to improve the quality of medical care for patients with brain cancer, using promising smart-sleep and non-invasive approaches of glioma treatment.

Anesthesia enables the painless performance of complex surgical procedures. However, the effects of anesthesia on the brain may not be limited only by its duration. Also, anesthetic agents may cause long-lasting changes in the brain. There is growing evidence that anesthesia can disrupt the integrity of the blood–brain barrier (BBB), leading to neuroinflammation and neurotoxicity. However, there are no widely used methods for real-time BBB monitoring during surgery. The development of technologies for an express diagnosis of the opening of the BBB (OBBB) is a challenge for reducing post-surgical/anesthesia consequences. In this study on male rats, we demonstrate a successful application of machine learning technology, such as artificial neural networks (ANNs), to recognize the OBBB induced by isoflurane, which is widely used in surgery. The ANNs were trained on our previously presented data obtained on the sound-induced OBBB with an 85% testing accuracy. Using an optical and nonlinear analysis of the OBBB, we found that 1% isoflurane does not induce any changes in the BBB, while 4% isoflurane caused significant BBB leakage in all tested rats. Both 1% and 4% isoflurane stimulate the brain’s drainage system (BDS) in a dose-related manner. We show that ANNs can recognize the OBBB induced by 4% isoflurane in 57% of rats and BDS activation induced by 1% isoflurane in 81% of rats. These results open new perspectives for the development of clinically significant bedside technologies for EEG-monitoring of OBBB and BDS.

Intraventricular hemorrhage is one of the most fatal forms of brain injury that is a common complication of premature infants. However, the therapy of this type of hemorrhage is limited, and new strategies are needed to reduce hematoma expansion. Here we show that the meningeal lymphatics is a pathway to remove red blood cells from the brain’s ventricular system of male human, adult and newborn rodents and is a target for non-invasive transcranial near infrared photobiomodulation. Our results uncover the clinical significance of phototherapy of intraventricular hemorrhage in 4-day old male rat pups that have the brain similar to a preterm human brain. The course of phototherapy in newborn rats provides fast recovery after intraventricular hemorrhage due to photo-improvements of lymphatic drainage and clearing functions. These findings shed light on the mechanisms of phototherapy of intraventricular hemorrhage that can be a clinically relevant technology for treatment of neonatal intracerebral bleedings.

Over sixty years, laser technologies have undergone a technological revolution and become one of the main tools in biomedicine, particularly in neuroscience, neurodegenerative diseases and brain tumors. Glioblastoma is the most lethal form of brain cancer, with very limited treatment options and a poor prognosis. In this study on rats, we demonstrate that glioblastoma (GBM) growth can be suppressed by photosensitizer-free laser treatment (PS-free-LT) using a quantum-dot-based 1267 nm laser diode. This wavelength, highly absorbed by oxygen, is capable of turning triplet oxygen to singlet form. Applying 1267 nm laser irradiation for a 4 week course with a total dose of 12.7 kJ/cm² firmly suppresses GBM growth and increases survival rate from 34% to 64%, presumably via LT-activated apoptosis, inhibition of the proliferation of tumor cells, a reduction in intracranial pressure and stimulation of the lymphatic drainage and clearing functions. PS-free-LT is a promising breakthrough technology in non- or minimally invasive therapy for superficial GBMs in infants as well as in adult patients with high photosensitivity or an allergic reaction to PSs.

The progress in brain diseases treatment is limited by the blood-brain barrier (BBB), which prevents delivery of the vast majority of drugs from the blood into the brain. In this study, we discover unknown phenomenon of opening of the BBBB (BBBO) by low-level laser treatment (LLLT, 1268 nm) in the mouse cortex. LLLT-BBBO is accompanied by activation of the brain drainage system contributing effective delivery of liposomes into glioblastoma (GBM). The LLLT induces the generation of singlet oxygen without photosensitizers (PSs) in the blood endothelial cells and astrocytes, which can be a trigger mechanism of BBBO. LLLT-BBBO causes activation of the ABC-transport system with a temporal decrease in the expression of tight junction proteins. The BBB recovery is accompanied by activation of neuronal metabolic activity and stabilization of the BBB permeability. LLLT-BBBO can be used as a new opportunity of interstitial PS-free photodynamic therapy (PDT) for modulation of brain tumor immunity and improvement of immuno-therapy for GBM in infants in whom PDT with PSs, radio- and chemotherapy are strongly limited, as well as in adults with a high allergic reaction to PSs.

The 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.

Oxana Semyachkina-Glushkovskaya, Inna Blokhina, Nikita Navolokin, Arina Evsukova, Georgy Karandin, Alexander Khorovodov, Andrey Terskov, Ivan Fedosov, Alexander Dubrovsky, Maria Tzoy, Vasily Ageev, Ilana Agranovich, Valeria Telnova, Anna Tsven, Jürgen Kurths. J Acupunct Meridian Stud 2022;15:43-9. https://doi.org/10.51507/j.jams.2022.15.1.43

The deposition of amyloid-β (Aβ) in the brain is a risk factor for Alzheimer’s disease (AD). Therefore, new strategies for the stimulation of Aβ clearance from the brain can be useful in preventing AD. Transcranial photostimulation (PS) is considered a promising method for AD therapy. In our previous studies, we clearly demonstrated the PS-mediated stimulation of lymphatic clearing functions, including Aβ removal from the brain. There is increasing evidence that sleep plays an important role in Aβ clearance. Here, we tested our hypothesis that PS at night can stimulate Aβ clearance from the brain more effectively than PS during the day. Our results on healthy mice show that Aβ clearance from the brain occurs faster at night than during wakefulness. The PS course at night improves memory and reduces Aβ accumulation in the brain of AD mice more effectively than the PS course during the day. Our results suggest that night PS is a more promising candidate as an effective method in preventing AD than daytime PS. These data are an important informative platform for the development of new noninvasive and nonpharmacological technologies for AD therapy as well as for preventing Aβ accumulation in the brain of people with disorder of Aβ metabolism, sleep deficit, elderly age, and jet lag.