Brain tissue is lacking in lymphatic vessels, necessitating a specialized system, known as the glymphatic system, for the delivery, transport, and removal of various components contained in cerebrospinal fluid (1, 2). The cerebrospinal fluid enters and circulates throughout the brain aided by cardiac-driven arterial pulsations. Astrocytes not only govern vascular tone, but also control fluid dynamics. Via astrocytic aquaporin-4 (AQP4) channels, cerebrospinal fluid then exchanges with fluid dispersed within the interstitial spaces of neuronal and glial tissue to facilitate water equilibrium, provide solutes, signaling molecules, and ions, and coordinate immune response (2). The glymphatic system drains into the meningeal lymphatic vessels and finally the peripheral lymphatic circulation, carrying with it metabolic waste and neurotoxic debris.
The glymphatic system is most active during sleep, exceeding waking circulation by up to ten times (1). The relatively new discovery of the glymphatic system and its nocturnal nature has ignited renewed interest in how sleep quality and duration can subsequently influence brain function (1, 2). Altered circadian rhythms and sleep disturbance have been tied to heightened prevalence of neurodegenerative and psychiatric disorders (3, 4). The circadian rhythm governs not only sleep, but also brain metabolism and chemical exchange in the brain. Poor or fragmented sleep upsets glymphatic dynamics, impeding clearance of metabolic waste and neurotoxic proteins (3). Inadequate sleep is also accompanied by oxidative stress, inflammatory signaling, and degradation of memory consolidation and neural plasticity (3). Restoration of proper circadian rhythm can attenuate sleep disturbances and reinstate the function of the glymphatic system, aiding in fluid homeostasis and metabolic clearance of proteins and other debris from the brain.
Elevated glymphatic flow ameliorates clearance of neurotoxic proteins while also potentiating synaptic remodeling, memory consolidation, and cognition (1, 2). During sleep, brain cell shrinkage and consequent interstitial space expansion, along with natural pulses of the vasculature, combine to bolster fluid flow. AQP4 water channels concentrated on astrocytic end feet that surround the perivascular spaces in the brain regulate fluid exchange (2). Vascular compliance, arterial pulsatility, AQP4 polarization, and other factors modulate cerebrospinal and interstitial fluid movement and transfer. α-syntrophin (Snta1) is a critical scaffolding protein that acts to preserve AQP4 polarization at astrocytic end feet (2). Research indicates that proper AQP4 placement is vital for adequate fluid exchange, with mislocalization potentially exacerbating neurodegeneration.
Proper astrocyte function, metabolic homeostasis, and vascular pulsatility are essential to promote robust cerebrospinal fluid dynamics (2). Aging, neurodegenerative disease, and brain injury are correlated with impaired glymphatic system activity. These conditions are associated with thickened basement membranes, blood vessel stiffness, a loss of AQP4 polarization, and diminished arterial pulsatility (1, 2). Poor fluid flow and exchange contributes to the buildup of toxic protein tangles, metabolic byproducts, and inflammatory mediators that collectively hinder neuronal signaling, drive oxidative stress, and compromise synaptic plasticity. Appropriate functioning of the meningeal lymphatic system is equally important for waste, solute, and other byproduct removal. Its performance is impacted by endothelial integrity, intracranial pressure, inflammatory burden, and vascular pulsatility (2).
Systemic inflammation profoundly alters glymphatic flow due to a heightened prevalence of circulating pro-inflammatory cytokines and promotion of endothelial dysfunction (2). Tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) weaken the tight junctions and activate the endothelial cells of the blood-brain barrier. Attenuated endothelial integrity disrupts the perivascular environment and causes depolarization of AQP4 channels. Subsequent reduced fluid exchange allows for accumulation of neurotoxic substances (2). Cytokines also lead to astrocyte stimulation and downstream cell structure remodeling, interrupting communication between astrocytes and the vasculature. Furthermore, chronic inflammation and endothelial activation amplify the generation of reactive oxygen species and stimulate matrix metalloproteinase activity (2). Oxidative stress and matrix metalloproteinases damage meningeal lymphatic vessels and slow lymph movement.
Historically, glymphatic imaging studies have relied upon the use of anesthesia to induce sleep (1). However, anesthesia is known to modify the natural characteristics of sleep. Such an effect prevents the investigation of glymphatic flow in true sleep. Novel approaches have been introduced that have enabled observation of blood and fluid dynamics during both sleep and wakefulness (1). It has since been elucidated that oscillated release of noreadrenaline from the locus coeruleus facilitates gradual vasomotion that drives glymphatic solute movement during sleep. Norepinephrine is a strong vasoconstrictor, and its oscillatory secretion acts as a pump to propel glymphatic fluid (1). Research suggests that norepinephrine dynamics are the key determinant of glymphatic clearance, even more-so than total amount of Rapid Eye Movement (NREM) sleep, Rapid Eye Movement (REM) sleep, or the strength or density of low-frequency brain waves during NREM sleep (1).
Given the newly clarified role of norepinephrine in sleep architecture and corresponding glymphatic system function, sleep aids that disrupt norepinephrine release may greatly impact glymphatic clearance during sleep (1). Anesthesia is recognized to suppress norepinephrine and vasomotion, thereby inhibiting glymphatic activity. Postoperative cognitive dysfunction occurs following anesthesia, and is associated with inferior recovery rates and augmented dementia risk (3). As a positive modulator of GABA receptors, Zolpidem (Ambien) elevates GABAergic transmission and tempers norepinephrine oscillations (1). Research has uncovered a correlation between Zolpidem use and dementia and Alzheimer’s disease risk (3). Sleep aids that provoke inhibitory transmission may interfere with the activity of the locus coeruleus, norepinephrine release, natural sleep architecture, and glymphatic performance. Studies have expressed concern that such disruption may increase the risk of developing dementia and other neurocognitive deficits (3). A recent narrative review suggested that chronic use of hypnotics, especially benzodiazepines, may restrain glymphatic clearance, promoting the accretion of amyloid-beta protein tangles in the brain (5).
Orexin is a neuropeptide that fosters wakefulness, and its dysregulated expression has been linked with Alzheimer’s disease (6). The commonly prescribed sleep aid, suvorexant, acts as a dual orexin receptor antagonist and has been shown to acutely lessen tau phosphorylation and amyloid-beta concentrations in the central nervous system. While its mechanisms of action have yet to be elucidated, orexin inhibition may block the chain of reactions that trigger activation of p38 MAPK, a kinase responsible for protein phosphorylation (6). Additionally, gamma-secretase, the enzyme that manufactures amyloid-beta plaques, is stimulated by beta-arrestin-2. By blocking the interaction between orexin receptors and beta-arrestin-2, suvorexant effectively halts gamma-secretase and ensuing amyloid-beta production (6). However, research in rat models demonstrated that both orexin A and B elevate norepinephrine release in the locus coeruleus (3). Orexin antagonists may thereby interfere with norepinephrine release and dampen glymphatic clearance. Based on these findings, it can be inferred that adrenergic receptor blockade by antipsychotic drugs also likely impairs glymphatic flow (3).
Several natural compounds have been shown to restore glymphatic flow and aid in the removal of metabolites and waste products as well as reduce brain edema. The Yi-Zhi-Fang-Dai formula, comprising a combination of ginkgo biloba, ginseng, cistanches herba, and grassleaf sweetflag rhizome, notably attenuated glial cell pyroptosis, neuroinflammation, microglial overactivation, astrocytic end feet swelling, and brain edema, while reestablishing AQP4 polarization in an animal model (7). These effects collectively averted blood-brain barrier damage, supported glymphatic function, facilitated amyloid-beta removal, and improved neuronal survival. In another study, the Chinese herbal medicine xueshuantong was found to enhance cerebral blood flow and enlarge meningeal lymphatic vessels, as well as elevate amyloid-beta efflux and decrease plaque size and density (8). Xueshuantong was also shown to upregulate the expression of anti-inflammatory cytokines IL-1β and IL-10, while lowering the pro-inflammatory cytokine IL-6, thereby diminishing microglia and astrocyte activation (8).
Two additional compounds observed to enhance glymphatic function include quercetin and resveratrol (9). Both polyphenols are purported to abate astrocyte and microglial inflammation that contributes to morphological changes and consequent impaired glymphatic flow. Resveratrol and quercetin downregulate MAPK-NFκB, JAK-STAT, and PI3-AKT pathways, thereby fostering a protective M2 shift (9). Furthermore, both compounds counter oxidative stress by elevating anti-inflammatory cytokines and vital antioxidant enzymes while suppressing attachment proteins. By dampening oxidative stress, enhancing mitophagy and mitochondrial performance, and reinforcing tight junctions, quercetin and resveratrol stabilize the blood-brain barrier and protect against gliosis (9). Resveratrol and quercetin also maintain the perivascular space and blood brain vessels, as well as preserve endothelial function and reverse vascular damage, culminating in restored fluid homeostasis throughout the brain. Resveratrol in particular activates the SIRT-1 protective pathway which in turn stimulates Nrf2, a critical antioxidant pathway (9). MMP-9 is subsequently reduced and the beta-dystroglycan anchors conserved which lessens blood-brain barrier injury and AQP4 mislocalization.
The ketogenic diet, which prompts the creation of ketone bodies, has been implicated in the abatement of amyloid-beta deposition characteristic of neurodegenerative disease. β-hydroxybutyrate (BHB) is the main component of ketone bodies and has been studied for the purpose of bolstering glymphatic system function (10). BHB supplementation has been found to notably increase AQP4 polarization and consequently lower cerebral edema, indicating improved glymphatic dynamics. As an epigenetic regulator, BHB inhibits HDAC1 and HDAC3, resulting in the upregulation of p300. These effects serve to potentiate α1-syntrophin expression which plays a role in maintaining AQP4 polarization (10). Melatonin is another endogenous molecule synthesized in the pineal gland, and participates in the regulation of circadian rhythm. Melatonin has been demonstrated to ameliorate sleep structure and corresponding glymphatic dynamics (3). It does so in part by influencing the expression of the circadian rhythm protein, Per2, and diminishing expression of the astrocytic activator, glial fibrillary acidic protein, thereby restoring astrocytic AQP4 polarization. Melatonin alleviates edema while augmenting cerebral blood flow, and also supports repair of the blood-brain barrier (3). Such actions assist in waste and amyloid-beta clearance from the brain.
The gut microbiome has also been linked with brain metabolism and glymphatic function through the gut-brain axis (11). Short-chain fatty acids (SCFAs) derived from microbial fermentation of dietary fibers are able to penetrate the blood-brain barrier and affect AQP4 polarization. Butyrate has been linked with enhanced fluid flow, waste removal, and blood-brain barrier integrity by moderating neuroinflammation. SCFAs also diminish astrocyte activation by lowering pro-inflammatory cytokines as well as the infiltration of Th1 and Th17 lymphocytes (11). SCFAs modulate the vagus nerve which plays a role in regulating glymphatic dynamics through cholinergic signaling and anti-inflammatory acetylcholine release. Moreover, antibiotic regimens induce morphological and functional alterations in microglia leading to inappropriate inflammatory responses and heightened susceptibility to neurodegenerative processes. SCFAs, in contrast, protect against microglial activation, elicit anti-inflammatory polarization, and impact microglial gene expression to ensure appropriate maturation and function (11). A eubiotic state supports neurohormonal signaling and neuroactive compound production, consequently improving circadian rhythm, promoting glymphatic flow, and preserving the structure of both the blood-brain barrier and the blood-cerebral spinal fluid barrier.
Essential omega-3 fatty acids have additionally been positively correlated with amelioration of glymphatic function and microvascular health (12). Omega-3 fatty acids concentrate in cerebral tissues and serve critical signaling functions. Omega-3 fatty acids promote glymphatic system circulation to advance phosphorylated tau protein elimination from the brain. They do so by reinstating AQP4 polarization via stimulation of PDGF-B/PDGFRβ/DAPC signaling, resulting in an upregulation of LAMININ γ1, AGRIN, and α-syntrophin. Furthermore, serum zinc has been positively correlated with the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, a marker for evaluating glymphatic system activity (13). Zinc exhibits neuroprotective properties as an antioxidant and is recognized for its role in mood regulation. It has been suggested that this antioxidant effect may bolster glymphatic dynamics.
Last but not least, exercise is a potent modulator of glymphatic and lymphatic function (2). Physical activity boosts glymphatic efficiency by supporting vascular health and pulsatility, enhancing arterial compliance, decreasing inflammation, and promoting cerebral blood flow. Exercise prompts increased expression of antioxidant enzymes that dampen oxidative stress, and exerts an immunomodulatory effect that quells inflammatory processes (2). Reduction of pro-inflammatory cytokines acts to temper microglial and astrocyte activation, thereby reestablishing AQP4 channel polarization and expression on astrocytic endfeet. Furthermore, exercise is profoundly involved in vascular adaptations, augmenting pro-angiogenic factors and vascular endothelial growth factor to elevate capillary density. It additionally activates PI3K/Akt and MAPK/ERK implicated in endothelial health and vascular remodeling (2). Heightened blood flow during physical activity triggers activation of endothelial nitric oxide synthase, giving rise to the vasodilator nitric oxide, as well as prostacyclin, culminating in better arterial compliance and pulsatility. Physical activity also serves to regulate circadian rhythm and improve sleep quality (2). By bolstering vascular health and arterial compliance, diminishing inflammation, restoring sleep dynamics, and intensifying perfusion, exercise plays a key part in glymphatic and meningeal lymphatic system function.
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