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Photobiomodulation Under Electroencephalographic Controls of Sleep for Stimulation of Lymphatic Removal of Toxins from Mouse Brain

The meningeal lymphatic vessels (MLVs) play an important role in the removal of toxins from the brain. The development of innovative technologies for the ...

Saratov State University

With the increase in the aging population, the global number of people with Alzheimer's disease (AD) progressively increased worldwide. The situation is aggravated by the fact that there is no the effective pharmacological therapy of AD. Photobiomodulation (PBM) is non-pharmacological approach that has shown very promising results in the therapy of AD in pilot clinical and animal studies. However, the mechanisms of therapeutic effects of PBM for AD are poorly understood. In this study on mice, we demonstrate that photodynamic effects of 5-aminolevulenic acid and laser 635 nm cause reduction of network of the meningeal lymphatic vessels (MLVs) leading to suppression of lymphatic removal of beta-amyloid (Aβ) from the right lateral ventricle and the hippocampus. Using the original protocol of PBM under electroencephalographic monitoring of wakefulness and sleep stages in non-anesthetized mice, we discover that the 7-day course of PBM during deep sleep vs. wakefulness provides better restoration of clearance of Aβ from the ventricular system of the brain and the hippocampus. Our results shed light on the mechanism of PBM and show the stimulating effects of PBM on the brain lymphatic drainage that promotes transport of Aβ via the lymphatic pathway. The effects of PBM on the brain lymphatics in sleeping brain open a new niche in the study of restorative functions of sleep as well as it is an important informative platform for the development of innovative smart sleep technologies for the therapy of AD.

Mechanisms of phototherapy of Alzheimer's disease during sleep and wakefulness: the role of the meningeal lymphatics.

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/cm 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.

Transcranial Photosensitizer-Free Laser Treatment of Glioblastoma in Rat Brain.

There is strong evidence that augmentation of the brain's waste disposal system via stimulation of the meningeal lymphatics might be a promising therapeutic target for preventing neurological diseases. In our previous studies, we demonstrated activation of the brain's waste disposal system using transcranial photostimulation (PS) with a laser 1267 nm, which stimulates the direct generation of singlet oxygen in the brain tissues. Here we investigate the mechanisms underlying this phenomenon. Our results clearly demonstrate that PS-mediated stimulation of the brain's waste disposal system is accompanied by activation of lymphatic contractility associated with subsequent intracellular production of the reactive oxygen species and the nitric oxide underlying lymphatic relaxation. Thus, PS stimulates the brain's waste disposal system by influencing the mechanisms of regulation of lymphatic pumping.

Mechanisms of Photostimulation of Brain's Waste Disposal System: The Role of Singlet Oxygen.

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.

Machine Learning Technology for EEG-Forecast of the Blood-Brain Barrier Leakage and the Activation of the Brain's Drainage System during Isoflurane Anesthesia.

In this study on healthy male mice using confocal imaging of dye spreading in the brain and its further accumulation in the peripheral lymphatics, we demonstrate stronger effects of photobiomodulation (PBM) on the brain's drainage system in sleeping vs. awake animals. Using the Pavlovian instrumental transfer probe and the 2-objects-location test, we found that the 10-day course of PBM during sleep vs. wakefulness promotes improved learning and spatial memory in mice. For the first time, we present the technology for PBM under electroencephalographic (EEG) control that incorporates modern state of the art facilities of optoelectronics and biopotential detection and that can be built of relatively cheap and commercially available components. These findings open a new niche in the development of smart technologies for phototherapy of brain diseases during sleep.

Technology of the photobiostimulation of the brain's drainage system during sleep for improvement of learning and memory in male mice.

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  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.

Article	Year
Mechanisms of phototherapy of Alzheimer's disease during sleep and wakefulness: the role of the meningeal lymphatics. Frontiers of optoelectronics\| PubMed ID: 37721564	2023
Transcranial Photosensitizer-Free Laser Treatment of Glioblastoma in Rat Brain. International journal of molecular sciences\| PubMed ID: 37762000	2023
Mechanisms of Photostimulation of Brain's Waste Disposal System: The Role of Singlet Oxygen. Advances in experimental medicine and biology\| PubMed ID: 37845438	2023
Machine Learning Technology for EEG-Forecast of the Blood-Brain Barrier Leakage and the Activation of the Brain's Drainage System during Isoflurane Anesthesia. Biomolecules\| PubMed ID: 38002287	2023
Technology of the photobiostimulation of the brain's drainage system during sleep for improvement of learning and memory in male mice. Biomedical optics express\| PubMed ID: 38223185	2024
Different Effects of Phototherapy for Rat Glioma during Sleep and Wakefulness. Biomedicines\| PubMed ID: 38397864	2024

Maria Manzhaeva

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