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

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.

Low-Level Laser Treatment Induces the Blood-Brain Barrier Opening and the Brain Drainage System Activation: Delivery of Liposomes into Mouse Glioblastoma.

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.

GB20 Pharmacopuncture As a Potential Method for Brain Drug Delivery via the Perivascular Spaces.

Background: The development of new methods of drug brain delivery is a crucial step for the effective therapy of the brain diseases. Pharma- and acupuncture are the forms of alternative therapy of the brain pathology, including an increase in the permeability of blood-brain barrier. However, the mechanisms of pharma- and acupuncture-mediated effects on the brain physiology remain not fully understood. Results: This pilot study on healthy mice clearly demonstrates the Evans Blue spreading in the mouse head and in the brain via the perivascular spaces (PVSs) of the trigeminal structure and the cribriform plate after the dye injection into the Feng Chi point (Galbladder 20, GB20). Conclusion: These results suggest that pharmacopuncture at GB20 can be a perspective method for brain drug delivery via PVSs.

Intranasal Delivery of Liposomes to Glioblastoma by Photostimulation of the Lymphatic System.

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.

Night Photostimulation of Clearance of Beta-Amyloid from Mouse Brain: New Strategies in Preventing Alzheimer's Disease.

The deposition of amyloid-ß (Aß) in the brain is a risk factor for Alzheimer's disease (AD). Therefore, new strategies for the stimulation of Aß 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 Aß removal from the brain. There is increasing evidence that sleep plays an important role in Aß clearance. Here, we tested our hypothesis that PS at night can stimulate Aß clearance from the brain more effectively than PS during the day. Our results on healthy mice show that Aß clearance from the brain occurs faster at night than during wakefulness. The PS course at night improves memory and reduces Aß 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 Aß accumulation in the brain of people with disorder of Aß metabolism, sleep deficit, elderly age, and jet lag.

Photobiomodulation of lymphatic drainage and clearance: perspective strategy for augmentation of meningeal lymphatic functions.

There 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.

Optical properties of brain tissues at the different stages of glioma development in rats: pilot study.

In this paper, measurements of the optical properties (diffuse reflectance, total and collimated transmittance) of brain tissues in healthy rats and rats with C6-glioma were performed in the spectral range from 350 to 1800 nm. Using these measurements, characteristic tissue optical parameters, such as absorption coefficient, scattering coefficient, reduced scattering coefficient, and scattering anisotropy factor were reconstructed. It was obtained that the 10-day development of glioma led to increase of absorption coefficient, which was associated with the water content elevation in the tumor. However, further development of the tumor (formation of the necrotic core) led to decrease in the water content. The dependence of the scattering properties on the different stages of model glioma development was more complex. Light penetration depth into the healthy and tumor brain was evaluated.

Pilot study of transcranial photobiomodulation of lymphatic clearance of beta-amyloid from the mouse brain: breakthrough strategies for non-pharmacologic therapy of Alzheimer's disease.

In this pilot study, we analyzed effects of transcranial photobiomodulation (tPBM, 1267 nm, 32 J/cm2) on clearance of beta-amyloid (Aß) from the mouse brain. The immunohistochemical and confocal data clearly demonstrate the significant reduction of deposition of Aß plaques in mice after tPBM vs. untreated animals. The behavior tests showed that tPBM improved the cognitive, memory and neurological status of mice with Alzheimer's disease (AD). Using of our original method based on optical coherence tomography (OCT) analysis of clearance of gold nanorods (GNRs) from the brain, we proposed possible mechanism underlying tPBM-stimulating effects on clearance of Aß via the lymphatic system of the brain and the neck. These results open breakthrough strategies for a non-pharmacological therapy of Alzheimer's disease and clearly demonstrate that tPBM might be a promising therapeutic target for preventing or delaying Alzheimer's disease.

Phenomenon of atypical vascular effects of epinephrine and an increase of photodynamic response by nitroglycerin in rats with colon adenocarcinoma: adrenergic and nitrergic mechanisms and novel applied aspects.

Using an original model of stress-induced colon adenocarcinoma, we uncover atypical vasorelaxation effects of a mucosa injection of epinephrine assessed by laser speckle contrast imaging and a significant increase of fluorescent intensity of 5-ALA/PpIX from malignant colon tissues by a mucosa injection of nitroglycerine. We clearly demonstrate a high activity of adrenergic and nitrergic mechanisms underlying this phenomenon and discuss their application in improving of optical approaches for effective diagnosis of gastrointestinal cancer.

Photodynamic opening of the blood-brain barrier and pathways of brain clearing.

A new application of the photodynamic treatment (PDT) is presented for the opening of blood-brain barrier (BBB) and the brain clearing activation that is associated with it, including the use of gold nanoparticles as emerging photosensitizer carriers in PDT. The obtained results clearly demonstrate 2 pathways for the brain clearing: (1) using PDT-opening of BBB and intravenous injection of FITC-dextran we showed a clearance of this tracer via the meningeal lymphatic system in the subdural space; (2) using optical coherence tomography and intraparenchymal injection of gold nanorods, we observed their clearance through the exit gate of cerebral spinal fluid from the brain into the deep cervical lymph node, where the gold nanorods were accumulated. These data contribute to a better understanding of the cerebrovascular effects of PDT and shed light on mechanisms, underlying brain clearing after PDT-related opening of BBB, including clearance from nanoparticles as drug carriers.

Stress-Induced Stroke and Stomach Cancer: Sex Differences in Oxygen Saturation.

Sex differences in stress-related diseases such as stroke and stomach cancer are well established, but the mechanisms underlying this phenomenon remain unknown. Despite the fact that sexual hormones play an important role in the high resistance of females to harmful effects of stress compared with males, the regulation of oxygenation status can be a potential factor, which might explain sex differences in stress-induced cerebrovascular catastrophes in newborn rats and in mutagens activation in adult rats with stomach cancer.