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51BREAKTHROUGH STRATEGIES OF STIMULATION OF THE CEREBRAL LYMPHATICS
DURING SLEEP
OXANA SEMYACHKINA-GLUSHKOVSKAYA1,2, THOMAS PENZEL1,3, JÜRGEN KURTHS1,4, VALERY
TUCHIN1,5,6
1Saratov State University, Astrakhanskaya str., 83, Saratov, 410012, Russia 2Physics Department, Humboldt University, Newtonstrasse 15, 12489 Berlin, Germany 3Advanced Sleep Research GmbH, Berlin, Germany, Chariteplatz 1, 10117 Berlin, Germany 4Potsdam Institute for Climate Impact Research, Telegrafenberg A31, 14473 Potsdam, Germany 5Institute of Precision Mechanics and Control, Russian Academy of Science, Saratov, Russia 6National Research Tomsk State University, Tomsk, Russia
glushkovskaya@mail. ru
Abstract
There is an intensive growing body of evidence that sleep and the lymphatics play a crucial role in keeping the health of the central nervous system (CNS) via the night activation of drainage of CNS tissues and clearance of metabolites and neurotoxins. The ability to stimulate the brain drainage and clearing function during sleep might be a promising strategy in developing of innovative methods in neurorehabilitation therapy. Here we discuss that sleep is the natural driving factor for activation of the cerebral lymphatics and is a platform for development of innovative optical strategies in stimulation of drainage and cleaning function of the cerebral lymphatics. We strongly believe that this pioneering step will motivate researchers and industrial partners to develop novel promising devices for neurorehabilitaion medicine based on the night stimulation of lymphatic functions.
1. Photostimulation of the lymphatic system
The transcranial photostimulation (tPS) is considered as a possible novel nonpharmacological and non-invasive promising strategy for prevention or delay of Alzheimer's disease (AD) [1-7], depression [8-13], Parkinson's disease [14], stroke [15,16], traumatic brain injuries [17,18], post-mastectomy lymphedema [19,20], and post-surgical swelling [21,22]. The PS, known as low-level laser therapy, was first proposed by Endre Mester in 1967 for stimulation of hair growth [23] and in 1971 for wound healing [24]. The PS has broadened to include near-infrared wavelengths 600-1200 nm. The better tissue penetration properties of near-infrared light, together with its good efficacy, made it the most popular wavelength range. The PS-mediated stimulation of lymphatic drainage and clearing function might be one of the mechanisms underlying an important role of PS in neurorehabilition [25]. Due to a good penetration of PS into the brain cortex, tPS can stimulate the meningeal lymphatic vessels (MLVs). In our recent pilot study on mice with the injected AD model, we have clearly demonstrated that 9 days course of tPS (1267 nm, 32 J/cm2 97 ) strongly reduces Ap plaques in the brain which is associated with improving of the memory and neurocognitive deficit [1]. Based on our data on the real time monitoring of lymphatic clearance of gold nanorods (GNRs) from the cortex, the hyppocampus, the right ventricle, and the cisterna magna, we have proposed that the tPS-mediated stimulation of lymphatic drainage might be a possible mechanism underlying the tPS-elimination of Ap from the brain. These results open breakthrough strategies for a non-pharmacological therapy of AD and give strong evidence that tPS might be a promising therapeutic target for preventing or delaying AD. We investigated possible mechanisms of tPS-stimulation of lymphatic drainage and clearance [26,27]. Our results demonstrate that already low PS doses (1267 nm, 5 and 10 J/cm2) cause relaxation of the mesenteric LVs and increase their permeability to fluorescent macrophages via a decrease of expression of tight junction and transendothelial resistance. We hypothesized that a PS-mediated increase in the permeability of the lymphatic endothelium might be the mechanism of transport of macromolecules and cells in the narrow cerebral lymphatic vessels (LVs). The increasing of permeability of the lymphatic endothelium is the key factor underlying lipids diffusion and macromolecules from the tissues to LVs, which may help to explain why the adipose tissue is always located adjacent to collecting lymphatics and lymph nodes [28-30]. The transport of macromolecules across the collecting LVs is coupled to water flux and sensitive to lymph pressure [28]. The inherent permeability of LVs is sufficient to broadcast antigens, passing within lymph to the cLNs [29]. Kuan et al. clearly demonstrated that the delivery of soluble antigens such as FITC-conjugated endogenous proteins and Ea-GFP is possible due to the permeability of the LVs [29]. This process exposes a large community of endocytic and phagocytic cells, particularly dendritic cells and macrophages. Physiological mechanisms underlying the lymphatic permeability to macromolecules remain, however, unknown. The possible role of Lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) and Chemokine C-C motif ligand 21 (CCL21) might be involved in the regulation of migration of immune cells through the lymphatic endothelium. The Lyve-1 is a transmembrane receptor of hyaluronan, which regulates cell migration in the course of wound healing, inflammation, and embryonic morphogenesis [31]. This protein is expressed primarily on both the luminal and abluminal surface of the lymphatic endothelium [31,32] and plays an important role in hyaluronan transport providing for migration of immune cells [33]. The CCL21 is secreted by the lymphatic endothelial cells and is involved in activation of T-lymphocyte movement, migration of the lymphocytes to other organs, and dendritic cells into the lymph nodes [34]. Nitric oxide
(NO) can be another modulating factor of lymph flow [3 5-40]. There are multiple sources of NO that could influence on the LVs funtions: 1) NO production from the endothelial nitric synthase in the lymphatic endothelium; 2) NO generation from the inducible nitric synthase in immune cells; 3) NO release from neural nitric synthase in the parenchyma or the perivascular lymphatic nerves [38,40-43], 4) countercurrent exchange of NO from adjacent arteries or veins. The predominant NO production in the LVs occurs in the valve-bulb region [44,45]. The high-shear force of lymph flowing through the open valve leaflets contributes to elevating of NO levels near the valve. The NO-mediated modulation of valves closing and opening coordinates the flow of lymph in the LVs [46]. In sum, the data above open new strategies for an alternative non-pharmacological therapy of brain diseases via PS modulation of lymphatic mechanisms of drainage and clearance of CNS tissues.
Figure 1'.Schematic illustration ofpossible PS-stimulation of the lymphatic clearance of RBCs from the brain after ICH. The PS applied during deep sleep (SWA) increases the drainage and clearing functions of the MLVs, which provide the transport of RBCs into the dcLNs. Two systems of photo-detection and measurement of the lymph flow (see Section "Measurement of the lymph flow ") control the intensity of PS and the lymphatic response to PS that is automatically analyzed on PC.
2. Potential stimulatory effects of deep sleep on drainage and clearance of the brain.
Sleep can be the natural driving factor for activation of the drainage and clearance of the brain via the lymphatics. The functions of sleep have been speculated already in ancient works such as "Aristotle's Theory of 'Sleep and Dreams'" [47]. However, only recently researchers have discovered that sleep has a crucial function of clearance of metabolites and neurotoxic wastes from the brain [48,49]. The clearance of toxic proteins such as beta-amyloid (AP) [50] and tau [51] from the brain strongly depends on sleep and neural activity [49,52-54]. Notice that not all stages of sleep are involved in the drainage and clearing functions of the brain. The electrical brain activity measured by the electroencephalography (EEG) during wakefulness is characterized by a small amplitude pattern. During most part of sleep, called non-rapid eye movement (NREM) sleep, which accounts 80% of total time of sleep, EEG exhibits a large amplitude oscillatory pattern with a slow wave activity (SWA, one second long) periodicity. This SWA, known as deep sleep, plays a crucial role in
the restorative functions and quality of sleep [55,56]. The deep sleep or SWA is actively discussed in recent publications as the main mechanisms of activation of the drainage and clearing functions of the brain. Indeed, Xie et al. demonstrated that cerebral spinal fluid (CSF) tracer influx into the mouse brain is largely reduced by 95% in the awake state [49]. However, during deep sleep tracer fast moves along the interstitial space and the parenchymal spaces that are increased by 60% compared with the awakeness. Based on the studies with humans Fultz et al. reported the high CSF and hemodynamic oscillation during SWA illustrating a potential bridge between NREM and activation of the drainage function of the brain [48]. These findings hint a potential bridge between deep sleep and activation of the repair and restorative functions of the cerebral lymphatics. Many studies have shown that the methods for an enhance of SWA demonstrate the efficacy for therapy of such serious neurodegenerative diseases such as AD [57], schizophrenia [58], and also in normal aging process [59]. The effectiveness of SWA enhancement for improvement of verbal declarative memory [60], object location memory [61], and picture memory [62] has been shown in several human studies.
Taken together the facts about the crucial function of deep sleep (SWA) in the drainage and clearing functions of the brain as well as about PS-mediated effects on MLVs, we hypothesize that PS-stimulation of the lymphatic drainage and clearance during deep sleep might be a promising tool for clearance of toxins such as Ap, red blood cells (RBSs), and waste products from the brain (see Figure 1).
This work was supported by RF Governmental Grant № 075-15-2019-1885, Grant from RSF № 20-15-00090 and 19-1500201, Grant from RFBR 19-515-55016 China a, 20-015-00308-a.
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