The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.

Structural and functional brain connectivity, synaptic activity, and information processing require highly coordinated signal transduction between different cell types within the neurovascular unit and intact blood-brain barrier (BBB) functions. Here, we examine the mechanisms regulating the formation and maintenance of the BBB and functions of BBB-associated cell types. Furthermore, we discuss the growing evidence associating BBB breakdown with the pathogenesis of inherited monogenic neurological disorders and complex multifactorial diseases, including Alzheimer's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

The blood-brain barrier (BBB) is a highly specialized brain endothelial structure of the fully differentiated neurovascular system. In concert with pericytes, astrocytes, and microglia, the BBB separates components of the circulating blood from neurons. Moreover, the BBB maintains the chemical composition of the neuronal "milieu," which is required for proper functioning of neuronal circuits, synaptic transmission, synaptic remodeling, angiogenesis, and neurogenesis in the adult brain. BBB breakdown, due to disruption of the tight junctions, altered transport of molecules between blood and brain and brain and blood, aberrant angiogenesis, vessel regression, brain hypoperfusion, and inflammatory responses, may initiate and/or contribute to a "vicious circle" of the disease process, resulting in progressive synaptic and neuronal dysfunction and loss in disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others. These findings support developments of new therapeutic approaches for chronic neurodegenerative disorders directed at the BBB and other nonneuronal cells of the neurovascular unit.

Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years. Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA-ergic neuronal systems. Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc). Orexin supplementation represents a more sophisticated way to treat narcolepsy because it addresses the underlying cause of the disease and not just the symptoms. Research on orexin supplementation in the treatment of sleep disorders has strongly increased over the past two decades. This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy.© 2018 Wiley Periodicals, Inc.

Studies on plasma orexin-A levels in prodromal dementia with Lewy bodies (DLB) and the relationship with clinical manifestations are rare.To assess plasma orexin-A levels and evaluate the correlation with clinical features in patients with mild cognitive impairment with Lewy bodies (MCI-LB) and DLB.Plasma orexin-A levels were measured in 41 patients with MCI-LB, 53 with DLB, and 48 healthy controls (HCs). Informant-based history, neurological examinations, neuropsychological assessments, laboratory tests, and neuroimaging were collected and the correlation between orexin-A and various indicators evaluated.Plasma orexin-A levels in patients with MCI-LB (1.18±0.33 ng/mL, p = 0.014) or DLB (1.20±0.44 ng/mL, p = 0.011) were significantly higher than in HCs (1.02±0.32 ng/mL) and associated with gender and age. DLB patients with fluctuating cognition (FC) (1.01±0.23 versus 1.31±0.50, p = 0.007) or parkinsonism (PARK) (0.98±0.19 versus 1.25±0.47, p = 0.030) had significantly lower plasma orexin-A levels than subjects without FC or PARK. Plasma orexin-A levels were significantly negatively correlated with irritability and UPDRS-III scores and significantly positively correlated with disinhibition scores.This is the first report in which elevated plasma orexin-A levels were observed in patients with MCI-LB or DLB. In addition, lower orexin-A levels were found in patients with DLB and FC or PARK compared with HCs. The plasma orexin-A levels were associated with the presence of core features and motor and neuropsychiatric symptoms in patients with MCI-LB and DLB.

目的 探讨血浆促食欲素A水平与路易体痴呆核心临床症状的相关性。方法 共纳入2019年1月至2021年12月首都医科大学附属北京天坛医院诊断与治疗的51例路易体痴呆患者以及性别、年龄、受教育程度相匹配的46例认知功能正常对照者，采用简易智能状态检查量表（MMSE）和蒙特利尔认知评价量表（MoCA）评估整体认知功能、临床痴呆评价量表（CDR）评估痴呆严重程度、日常生活活动能力量表（ADL）评估日常生活活动能力、汉密尔顿抑郁量表17项（HAMD-17）评估抑郁严重程度、神经精神科问卷（NPI）评估精神行为，测定血浆食欲素A水平；单因素和多因素Logistic回归分析筛查路易体痴呆影响因素，Pearson相关分析和偏相关分析探究血浆促食欲素A与路易体痴呆核心临床症状的相关性，多因素线性逐步回归分析探究血浆促食欲素A与神经心理学测验的线性相关关系。结果 路易体痴呆患者MMSE（Z=-8.387，P=0.000）和MoCA（Z=-8.479，P=0.000）评分均低于对照者，CDR（Z=-9.072，P=0.000）、ADL（Z=-8.692，P=0.000）、HAMD-17（Z=-7.568，P=0.000）、NPI（Z=-8.270，P=0.000）评分和血浆促食欲素A水平（Z=-2.688，P=0.007）均高于对照者；核心临床症状中有波动性认知功能障碍和有帕金森综合征患者血浆促食欲素A水平低于无波动性认知功能障碍（Z=-2.172，P=0.030）和无帕金森综合征（Z=-1.981，P=0.048）患者。Logistic回归分析显示，饮酒史是避免发生路易体痴呆的独立保护因素（OR=0.278，95% CI： 0.095~0.808； P=0.019）；血浆促食欲素A水平升高是路易体痴呆的独立危险因素（OR=6.878，95% CI： 1.241~38.137； P=0.027）。相关分析显示，血浆促食欲素A水平仅与核心临床症状中帕金森综合征呈负相关（r=-0.322，P=0.043）。多因素线性逐步回归分析显示，血浆促食欲素A与神经心理学测验评分无线性相关关系（均P>0.05）。结论 路易体痴呆患者血浆促食欲素A水平高于认知功能正常老年人，血浆促食欲素A水平升高更易罹患路易体痴呆，但可降低核心临床症状中帕金森综合征的发生率，促食欲素能系统功能失调可能是路易体痴呆的潜在发生机制。

Orexins A and B are peptides produced mainly by hypothalamic neurons that project to numerous brain structures. We have previously demonstrated that rat cortical neurons express both types of orexin receptors, and their activation by orexins initiates different intracellular signals. The present study aimed to determine the effect of orexins on the Akt kinase activation in the rat neuronal cultures and the significance of that response in neurons subjected to hypoxic stress. We report the first evidence that orexins A and B stimulated Akt in cortical neurons in a concentration- and time-dependent manner. Orexin B more potently than orexin A increased Akt phosphorylation, but the maximal effect of both peptides on the kinase activation was very similar. Next, cultured cortical neurons were challenged with cobalt chloride, an inducer of reactive oxygen species and hypoxia-mediated signaling pathways. Under conditions of chemical hypoxia, orexins potently increased neuronal viability and protected cortical neurons against oxidative stress. Our results also indicate that Akt kinase plays an important role in the pro-survival effects of orexins in neurons, which implies a possible mechanism of the orexin-induced neuroprotection.

Orexin-A, a neuropeptide secreted by hypothalamic neurons, may be neuroprotective in many neurological conditions such as cerebral ischaemia. One mechanism postulated to be involved in the neuroprotection by Orexin-A is the induction of hypoxia inducible factor 1 alpha (HIF-1α). Parkinson's disease (PD) is a progressive neurodegenerative disorder and mitochondrial dysfunction has been demonstrated to play a role in its pathogenesis. Mitochondrial dysfunction may cause reduction of O2 consumption and subsequently activate prolyl hydroxylase, which leads to decreased level of HIF-1α. In this study, we used MPP(+)-treated SH-SY5Y cells as an in vitro cellular model of PD to test the role of Orexin-A as an inducer of HIF-1α. Our results showed that Orexin-A not only induced HIF-1α but also activated downstream targets of HIF-1α, such as vascular endothelial growth factor and erythropoietin. Thus, Orexin-A treatment attenuated MPP(+)-induced cell injury and this effect was blocked when HIF-1α was suppressed. Hence, we conclude that induction of HIF-1α is one of the mechanisms involved in the neuroprotection by Orexin-A. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Brain ischemia causes immediate and delayed cell death that is exacerbated by inflammation. Recent studies show that hypocretin-1/orexin-A (Hcrt-1) reduces ischemic brain injury, and Hcrt-positive neurons modulate infection-induced inflammation. Here, we tested the hypothesis that Hcrt plays a protective role against ischemia by modulating inflammation.Orexin/ataxin-3 (AT) mice, a transgenic strain in which Hcrt-producing neurons degenerate in early adulthood, and wild-type mice were subjected to transient middle cerebral artery occlusion (MCAO). Infarct volume, neurological score, and spontaneous home cage activity were assessed. Inflammation was measured using immunohistochemistry, ELISA, and assessment of cytokine mRNA levels.Infarct volumes 24 and 48 hours after MCAO were significantly larger, neurological score was worse, and spontaneous activity decreased in AT compared with wild-type mice. Macrophage/microglial infiltration and myeloperoxidase-positive cells were higher in AT compared with wild-type mice. Pre-MCAO intracerebroventricular injection of Hcrt-1 significantly reduced infarct volume and macrophage/microglial infiltration in both genotypes and improved neurological score in AT mice. Post-MCAO treatment decreased infarct size in both wild-type and AT mice, but had no effect on neurological score in either genotype. Microglia express the Hcrt-1 receptor after MCAO. Tumor necrosis factor-α production by lipopolysaccharide-stimulated microglial BV2 cells was significantly reduced by Hcrt-1 pretreatment. Sham AT mice exhibit increased brain tumor necrosis factor-α and interleukin-6 mRNA, suggesting chronic inflammation.Loss of Hcrt neurons in AT mice resulted in worsened stroke outcomes, which were reversed by administration of exogenous Hcrt-1. The mechanism underlying Hcrt-mediated neuroprotection includes attenuation of inflammatory responses after ischemic insult.

Constipation is a common symptom in dementia, and the cause is controversial. Rare clinical studies focused on plasma orexin-A levels and constipation in dementia.To evaluate the associations between orexin-A and constipation in patients with cognitive impairment.A total of 21 patients with mild cognitive impairment (MCI), 142 with Alzheimer's disease (AD), and 57 with Lewy body dementia (LBD) were conducted. Besides informant-based history, neurological examinations or neuropsychological assessments, plasma levels of orexin-A, and constipation were assessed. The associations between orexin-A and constipation were evaluated by logistic regression models.There were 47/220 (21.36%) cognitive impairment patients having constipation, and the proportion of constipation in LBD (61.40%) was significantly higher than AD (5.63%) and MCI (19.05%). No significant age or sex differences in the prevalence of constipation were found in the MCI, AD, and LBD groups. We found the cognitive impairment patients with constipation had lower levels of plasma orexin-A [1.00 (0.86, 1.28) versus 1.29 (1.01, 1.50) ng/ml, p < 0.001] than those without. And the plasma levels of orexin-A were significantly associated with the occurrence of constipation after adjusting for all variables in all patients with cognitive impairment (OR = 0.151, 95% CI: 0.042-0.537, p = 0.003). And the same finding was more prominent in the LBD group (p = 0.048).The decrease of plasma level of orexin-A is closely associated with the occurrence of constipation. Orexin-A has an intestinal protective effect and is involved in the gastrointestinal symptoms of patients with cognitive impairment.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

The brain is supplied by an elaborate vascular network that originates extracranially and reaches deep into the brain. The concept of the neurovascular unit provides a useful framework to investigate how neuronal signals regulate nearby microvessels to support the metabolic needs of the brain, but it does not consider the role of larger cerebral arteries and systemic vasoactive signals. Furthermore, the recently emerged molecular heterogeneity of cerebrovascular cells indicates that there is no prototypical neurovascular unit replicated at all levels of the vascular network. Here, we examine the cellular and molecular diversity of the cerebrovascular tree and the relative contribution of systemic and brain-intrinsic factors to neurovascular function. Evidence supports the concept of a 'neurovascular complex' composed of segmentally diverse functional modules that implement coordinated vascular responses to central and peripheral signals to maintain homeostasis of the brain. This concept has major implications for neurovascular regulation in health and disease and for brain imaging.© 2021. Springer Nature America, Inc.

Cerebral endothelial cells and their linking tight junctions form a unique, dynamic and multi-functional interface, the blood-brain barrier (BBB). The endothelium is regulated by perivascular cells and components forming the neurovascular unit. This review examines BBB and neurovascular unit changes in normal aging and in neurodegenerative disorders, particularly focusing on Alzheimer disease, cerebral amyloid angiopathy and vascular dementia. Increasing evidence indicates BBB dysfunction contributes to neurodegeneration. Mechanisms underlying BBB dysfunction are outlined (endothelium and neurovascular unit mediated) as is the BBB as a therapeutic target including increasing the uptake of systemically delivered therapeutics across the BBB, enhancing clearance of potential neurotoxic compounds via the BBB, and preventing BBB dysfunction. Finally, a need for novel biomarkers of BBB dysfunction is addressed.

The vascular blood-brain barrier is a highly regulated interface between the blood and brain. Its primary function is to protect central neurons while signaling the presence of systemic inflammation and infection to the brain to enable a protective sickness behavior response. With increasing degrees and duration of systemic inflammation, the vascular blood-brain barrier becomes more permeable to solutes, undergoes an increase in lymphocyte trafficking, and is infiltrated by innate immune cells; endothelial cell damage may occasionally occur. Perturbation of neuronal function results in the clinical features of encephalopathy. Here, the molecular and cellular anatomy of the vascular blood-brain barrier is reviewed, first in a healthy context and second in a systemic inflammatory context. Distinct from the molecular and cellular mediators of the blood-brain barrier's response to inflammation, several moderators influence the direction and magnitude at genetic, system, cellular and molecular levels. These include sex, genetic background, age, pre-existing brain pathology, systemic comorbidity, and gut dysbiosis. Further progress is required to define and measure mediators and moderators of the blood-brain barrier's response to systemic inflammation in order to explain the heterogeneity observed in animal and human studies.© 2021. The Author(s).

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.Copyright © 2024. Published by Elsevier Inc.

Previous studies have shown that reduced sleep duration, sleep fragmentation, and decreased sleep quality in patients with Alzheimer's disease are related to dysfunction in orexin signaling. At the same time, blood-brain barrier disruption is considered an early biomarker of Alzheimer's disease. However, currently no report has examined how changes in orexin signaling relate to changes in the blood-brain barrier of patients who have Alzheimer's disease with sleep insufficiency. This cross-sectional study included 50 patients with Alzheimer's disease who received treatment in 2019 at Beijing Tiantan Hospital. Patients were divided into two groups: those with insufficient sleep (sleep duration ≤ 6 hours, n = 19, age 61.58 ± 8.54 years, 10 men) and those with normal sleep durations (sleep duration > 6 hours, n = 31, age 63.19 ± 10.09 years, 18 men). Demographic variables were collected to evaluate cognitive function, neuropsychiatric symptoms, and activities of daily living. The levels of orexin, its receptor proteins, and several blood-brain barrier factors were measured in cerebrospinal fluid. Sleep insufficiency was associated with impaired overall cognitive function that spanned multiple cognitive domains. Furthermore, levels of orexin and its receptors were upregulated in the cerebrospinal fluid, and the blood-brain barrier was destroyed. Both these events precipitated each other and accelerated the progression of Alzheimer's disease. These findings describe the clinical characteristics and potential mechanism underlying Alzheimer's disease accompanied by sleep deprivation. Inhibiting the upregulation of elements within the orexin system or preventing the breakdown of the blood-brain barrier could thus be targets for treating Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder that presents with cognitive impairment and behavioral disturbance. Approximately 5.5 million people in the United States live with AD, most of whom are over the age of 65 with two-thirds being woman. There have been major advancements over the last decade or so in the understanding of AD neuropathological changes and genetic involvement. However, studies of sex impact in AD have not been adequately integrated into the investigation of disease development and progression. It becomes indispensable to acknowledge in both basic science and clinical research studies the importance of understanding sex-specific differences in AD pathophysiology and pathogenesis, which could guide future effort in the discovery of novel targets for AD. Here, we review the latest and most relevant literature on this topic, highlighting the importance of understanding sex dimorphism from a molecular perspective and its association to clinical trial design and development in AD research field.Published by Elsevier B.V.

We explored the relationship between adiposity factors measured during mid-life and blood-brain barrier (BBB) integrity measured via the cerebrospinal fluid/serum (CSF/S) albumin ratio in late life. Adiposity factors included body mass index and blood levels of sex hormone binding globulin (SHBG) and leptin. Design. Retrospective analyses over 24 years within a longitudinal study.Population-based sample. Subjects. Eighty-one women.CSF/S albumin ratio.The CSF/S albumin ratio measured at age 70-84 years was higher amongst women who were overweight or obese (6.50 +/- 2.79 vs. 5.23 +/- 1.61, age-adjusted P = 0.012), and was inversely correlated with SHBG (age-adjusted r = -0.321, P < 0.005) at age 46-60 years. In stepwise regression models, SHBG predicted the CSF/S albumin ratio (beta = -0.017, R2 = 0.107, P = 0.007). The best model (R2 = 0.187) predicting CSF/S albumin ratio included SHBG, age group (age 46 years versus >46), overweight or obesity, and an age group by SHBG interaction.Lower levels of SHBG in mid-life were related to worse BBB integrity in women after 24 years in late life, even considering other adiposity factors. SHBG may be important for understanding sex hormone-mediated mechanisms in brain health or as an independent marker of adipose tissue, the largest endocrine organ.

Paroxysmal sleep disorders in children are important from both pathophysiological and clinical point of view. Correct diagnosis is crucial for further management. The aim of the present study was to identify peripheral markers of paroxysmal sleep disorders in children, which could improve diagnostics of these disorders. We compared serum levels of several putative biomarkers of neurological disorders, such as S100B protein, neuron specific enolase (NSE), orexin A, adiponectin, and insulin-like growth factor 1 (IGF-1) in pediatric patients suffering from sleep disturbances with those who additionally to parasomnia revealed also epilepsy.Fifty six children from 1 month to 18 years of age hospitalized in the Pediatric Neurology Clinic, Chair of Children and Adolescent Neurology, participated in this study. Polysomnographic diagnostics was indicated due to sleep disturbances. Examination was performed with the use of polysomnography and videoelectroencephalography Grass device. Blood samples were taken before registration of sleep, after 2.5 h of sleep or 0.5 h after occurrence of clinical seizures. Concentrations of S100B protein, NSE, orexin A, adiponectin, and IGF-1 were measured by specific ELISA methods.The obtained data showed that serum S100B level was significantly increased in children with epilepsy and clinical seizure attacks as compared to patients with parasomnia only. Atendency to enhanced serum S100B level was also seen in epileptic children without clinical seizures during polysomnographic recording. The level of orexin A was significantly decreased in epileptic children without seizures as compared to the hormone level in parasomnic patients, but was elevated in patients who experienced seizures during polysomnographic examination. As S100B is regarded to be a marker of blood brain barrier leakage and astrocyte damage, the data suggest an increase in BBB permeability in epileptic children, especially during seizure fits. Furthermore, the enhanced S100B serum level without changes in NSE activity may be interpreted rather as an evidence of the elevated secretion of this protein during seizures than of the damage of brain tissue. In contrast to S100B and orexin A level, serum concentration of adiponectin and IGF-1 as well as NSE activity did not significantly differ between the studied groups.Out of the five putative biomarkers measured, blood concentration of S100B and orexin A may be helpful in differentiating parasomnic pediatric patients with and without epilepsy.

Alzheimer's disease (AD) is the most prevalent dementia, pathologically featuring abnormal accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, while sleep, divided into rapid eye movement sleep (REM) and nonrapid eye movement sleep (NREM), plays a key role in consolidating social and spatial memory. Emerging evidence has revealed that sleep disorders such as circadian disturbances and disruption of neuronal rhythm activity are considered as both candidate risks and consequence of AD, suggesting a bidirectional relationship between sleep and AD. This review will firstly grasp basic knowledge of AD pathogenesis, then highlight macrostructural and microstructural alteration of sleep along with AD progression, explain the interaction between accumulation of Aβ and hyperphosphorylated tau, which are two critical neuropathological processes of AD, as well as neuroinflammation and sleep, and finally introduce several methods of sleep enhancement as strategies to reduce AD-associated neuropathology. Although theories about the bidirectional relationship and relevant therapeutic methods in mice have been well developed in recent years, the knowledge in human is still limited. More studies on how to effectively ameliorate AD pathology in patients by sleep enhancement and what specific roles of sleep play in AD are needed.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

The blood-brain barrier (BBB) constitutes a critical barrier for the maintenance of central nervous system homeostasis. Brain microvascular endothelial cells line the vessel walls and express tight junction (TJ) complexes that restrict paracellular passage across the BBB, thereby fulfilling a crucial role in ensuring brain function. Hypoxia, an impaired O(2) delivery, is known to cause BBB dysfunction but the mechanisms that drive this disruption remain unclear. This study discloses the relevance of the master regulator of the hypoxic response, hypoxia-inducible factor-1 (HIF-1), in hypoxia-induced barrier disruption using the rat brain endothelial cell line RBE4. Hypoxic exposure rapidly induced stabilization of the HIF-1 oxygen-dependent alpha subunit (HIF-1α) concomitantly with BBB impairment and TJ disruption mainly through delocalization and increased tyrosine phosphorylation of TJ proteins. Similar observations were obtained by normoxic stabilization of HIF-1α using CoCl(2), deferoxamine, and dimethyloxalylglycine underlining the involvement of HIF-1 in barrier dysfunction particularly via TJ alterations. In agreement inhibition of HIF-1 stabilization by 2-methoxyestradiol and YC-1 improved barrier function in hypoxic cells. Overall our data suggests that activation of HIF-1-mediated signaling disrupts TJ resulting in increased BBB permeability.© 2014 Wiley Periodicals, Inc.

Chuanxiong rhizome has been widely used for the treatment of cerebral vascular disease in traditional Chinese medicine. The integrity of blood-brain barrier (BBB) is closely linked to the cerebral vascular disease. The protective effects of ligustilide, the major bioactive component in Chuanxiong rhizome, on cerebral blood vessels have been reported previously, but its effects and potential mechanism on BBB have not been entirely clarified. In the current work, the effects of ligustilide on BBB permeability and the underlying molecular mechanisms had been investigated using the model of BBB established by coculturing astrocytes and brain microvascular endothelial cells isolated from the rat brain. The ischemia-damaged model of BBB has been established with oxygen and glucose deprivation (OGD). Our results indicated that OGD significantly increased the permeability in the coculture BBB model. This OGD-induced increase in permeability could suppress by ligustilide in a concentration-dependent manner. Also, ligustilide promoted both gene and protein expression of tight junction proteins. Ligustilide suppressed the upregulation of HIF-1α, vascular endothelial growth factor, and AQP-4 in the BBB model induced by OGD. Collectively, all results have demonstrated that ligustilide is capable of reducing the permeability of BBB in vitro model induced by OGD through HIF-1α/vascular endothelial growth factor pathway and AQP-4, which provide a new target for the clinical application of ligustilide on BBB after stroke in future.

Increase of blood brain barrier (BBB) permeability after acute ischemia stroke is a predictor to intracerebral hemorrhage transformation (HT) for tissue plasminogen activator (tPA) thrombolysis and post-endovascular treatment. Previous studies showed that 2-h ischemia induced damage of BBB integrity and matrix metalloproteinase-2 (MMP-2) made major contribution to this disruption. A recent study showed that blocking beta 2-adrenergic receptor (beta 2-AR) alleviated ischemia-induced BBB injury by reducing hypoxia-inducible factor-1 alpha (HIF-1 alpha) level. In this study, we sought to investigate the interaction of HIF-1 alpha with MMP-2 and vascular endothelial growth factor (VEGF) in BBB injury after acute ischemia stroke. Rat suture middle cerebral artery occlusion (MCAO) model was used to mimic ischemia condition. Our results showed that ischemia produced BBB damage and MMP-2/9 upregulation was colocalized with Rhodamine-dextran leakage. Pretreatment with YC-1, a HIF-1 alpha inhibitor, alleviated 2-h ischemia-induced BBB injury significantly accompanied by decrease of MMP-2 upregulation. In addition, YC-1 also prevented VEGF-induced BBB damage. Of note, VEGF was shown to be colocalized with neurons but not astrocytes. Taken together, BBB damage was reduced by inhibition of interaction of HIF-1 alpha with MMP-2 and VEGF during acute cerebral ischemia. These findings provide mechanisms underlying BBB damage after acute ischemia stroke and may help reduce thrombolysis-and post-endovascular treatment-related cerebral hemorrhage.