RESUMO

Sleep is a physiological process that preserves the integrity of the neuro-immune-endocrine network to maintain homeostasis. Sleep regulates the production and secretion of hormones, neurotransmitters, cytokines and other inflammatory mediators, both at the central nervous system (CNS) and at the periphery. Sleep promotes the removal of potentially toxic metabolites out of the brain through specialized systems such as the glymphatic system, as well as the expression of specific transporters in the blood-brain barrier. The blood-brain barrier maintains CNS homeostasis by selectively transporting metabolic substrates and nutrients into the brain, by regulating the efflux of metabolic waste products, and maintaining bidirectional communication between the periphery and the CNS. All those processes are disrupted during sleep loss. Brain endothelial cells express the blood-brain barrier phenotype, which arises after cell-to-cell interactions with mural cells, like pericytes, and after the release of soluble factors by astroglial endfeet. Astroglia, pericytes and brain endothelial cells respond differently to sleep loss; evidence has shown that sleep loss induces a chronic low-grade inflammatory state at the CNS, which is associated with blood-brain barrier dysfunction. In animal models, blood-brain barrier dysfunction is characterized by increased blood-brain barrier permeability, decreased tight junction protein expression and pericyte detachment from the capillary wall. Blood-brain barrier dysfunction may promote defects in brain clearance of potentially neurotoxic metabolites and byproducts of neural physiology, which may eventually contribute to neurodegenerative diseases. This chapter aims to describe the cellular and molecular mechanisms by which sleep loss modifies the function of the blood-brain barrier.

Assuntos

RESUMO

Microvessels in the central nervous system (CNS) have one of the highest populations of pericytes, indicating their crucial role in maintaining homeostasis. Pericytes are heterogeneous cells located around brain microvessels; they present three different morphologies along the CNS vascular tree: ensheathing, mesh, and thin-strand pericytes. At the arteriole-capillary transition ensheathing pericytes are found, while mesh and thin-strand pericytes are located at capillary beds. Brain pericytes are essential for the establishment and maintenance of the blood-brain barrier, which restricts the passage of soluble and potentially toxic molecules from the circulatory system to the brain parenchyma. Pericytes play a key role in regulating local inflammation at the CNS. Pericytes can respond differentially, depending on the degree of inflammation, by secreting a set of neurotrophic factors to promote cell survival and regeneration, or by potentiating inflammation through the release of inflammatory mediators (e.g., cytokines and chemokines), and the overexpression of cell adhesion molecules. Under inflammatory conditions, pericytes may regulate immune cell trafficking to the CNS and play a role in perpetuating local inflammation. In this review, we describe pericyte responses during acute and chronic neuroinflammation.

Assuntos

RESUMO

Aging is a complex and detrimental process, which disrupts most organs and systems within the organisms. The nervous system is morphologically and functionally affected during normal aging, and oxidative stress has been involved in age-related damage, leading to cognitive decline and neurodegenerative processes. Sulforaphane (SFN) is a hormetin that activates the antioxidant and anti-inflammatory responses. So, we aimed to evaluate if SFN long-term treatment was able to prevent age-associated cognitive decline in adult and old female and male rats. Memory was evaluated in adult (15-month-old), and old (21-month-old) female and male Wistar rats after three months of SFN treatment. Young rats (4-month-old) were used as age controls. The antioxidant response induction, the redox state (GSH/GSSG), and oxidative damage were determined in the brain cortex (Cx) and hippocampus (Hc). Our results showed that SFN restored redox homeostasis in the Cx and Hc of adult rats, thus preventing cognitive decline in both sexes; however, the redox responses were not the same in males and females. Old rats were not able to recover their redox state as adults did, but they had a mild improvement. These results suggest that SFN mainly prevents rather than reverts neural damage; though, there might also be a range of opportunities to use hormetins like SFN, to improve redox modulation in old animals.

Assuntos

RESUMO

Overweight and obesity are now considered a worldwide pandemic and a growing public health problem with severe economic and social consequences. Adipose tissue is an organ with neuroimmune-endocrine functions, which participates in homeostasis. So, adipocyte hypertrophy and hyperplasia induce a state of chronic inflammation that causes changes in the brain and induce neuroinflammation. Studies with obese animal models and obese patients have shown a relationship between diet and cognitive decline, especially working memory and learning deficiencies. Here we analyze how obesity-related peripheral inflammation can affect central nervous system physiology, generating neuroinflammation. Given that the blood-brain barrier is an interface between the periphery and the central nervous system, its altered physiology in obesity may mediate the consequences on various cognitive processes. Finally, several interventions, and the use of natural compounds and exercise to prevent the adverse effects of obesity in the brain are also discussed.

RESUMO

The study of the regionalized function of the blood-brain barrier at the level of brain endothelial cells and pericytes is essential to understand the biological properties and molecular mechanisms regulating this biological barrier. The isolation of blood vessels from specific brain regions will allow to understand regional differences in susceptibility to pathological phenomena such as ischemia, traumatic brain injury, and neurodegenerative diseases, such as Alzheimer disease. Here, we propose an efficient and fast method to isolate brain endothelial cells and pericytes from a specific cerebral region. The isolated brain endothelial cells and pericytes are viable to perform conventional molecular and histological techniques such as Western blots, immunocytofluorescence, and scanning electron microscopy.

Assuntos

RESUMO

Sleep loss in the rat increases blood-brain barrier permeability to circulating molecules by disrupting interendothelial tight junctions. Despite the description of the ultrastructure of cerebral microvessels and the evidence of an apparent pericyte detachment from capillary wall in sleep restricted rats the effect of sleep loss on pericytes is unknown. Here we characterized the interactions between pericytes and brain endothelial cells after sleep loss using male Wistar rats. Animals were sleep-restricted 20 h daily with 4 h sleep recovery for 10 days. At the end of the sleep restriction, brain microvessels (MVs) were isolated from cerebral cortex and hippocampus and processed for Western blot and immunocytochemistry to evaluate markers of pericyte-endothelial cell interaction (connexin 43, PDGFR-ß), tight junction proteins, and proinflammatory mediator proteins (MMP9, A2A adenosine receptor, CD73, NFκB). Sleep restriction reduced PDGFR-ß and connexin 43 expression in MVs; in addition, scanning electron microscopy micrographs showed that pericytes were detached from capillary walls, but did not undergo apoptosis (as depicted by a reduced active caspase-3 expression). Sleep restriction also decreased tight junction protein expression in MVs and increased BBB permeability to low- and high-molecular weight tracers in in vivo permeability assays. Those alterations seemed to depend on a low-grade inflammatory status as reflected by the increased expression of phosphorylated NFκB and A2A adenosine receptor in brain endothelial cells from the sleep-restricted rats. Our data show that pericyte-brain endothelial cell interaction is altered by sleep restriction; this evidence is essential to understand the role of sleep in regulating blood-brain barrier function.

Assuntos

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Sleep loss increases blood-brain barrier permeability. As the blood-brain barrier and the blood-tissue barriers in the reproductive tract (blood-testis and blood-epididymis barriers) share common characteristics, we hypothesized that sleep restriction may also modify their barrier function. Previous reports showed that sleep loss decreased sperm viability and progressive fast mobility, which may be a consequence of altered blood-testis and blood-epididymis barrier. Therefore, we quantified changes in blood-testis and blood-epididymis barrier after sleep loss and related them to male fertility. Adult male Wistar rats were sleep restricted using the multiple-platform technique in a protocol of 20 hr daily sleep deprivation plus 4 hr of sleep recovery in the home-cage. At the 10th day, barrier permeability assays were performed with Na-fluorescein, 10 kDa Cascade blue-dextrans and Evans blue, and the expression of tight junction proteins, actin and androgen receptor was quantified. At the 10th day of sleep restriction and after sleep recovery days 1-7, males were placed with sexually receptive females, sexual behaviour was tested, and the percentage of pregnancies was calculated. Sleep restriction increased the barrier permeability to low- and high-molecular-weight tracers, and decreased the expression of tight junction proteins, actin and androgen receptor. Concomitantly, sleep restriction reduced the percentage of ejaculating males and the number of pregnancies. Sleep recovery for 2-3 days progressively re-established fertility, as indicated by a higher percentage of ejaculating males and impregnated females. In conclusion, chronic sleep loss alters fertility concomitantly with the disruption of the blood-tissue barriers at the reproductive tract, the mechanism involves androgen signalling.

Assuntos

RESUMO

Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and increased blood-brain barrier permeability.

Assuntos