Interaction of major facilitator superfamily domain containing 2A with the blood-brain barrier

The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood.The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function.It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier,in addition to the transport of lipids,such as docosahexaenoic acid,across the blood-brain barrier.Furthermore,an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases;however,little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier.This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier,including their basic structures and functions,cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier,and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability.This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date.This will not only help to elucidate the pathogenesis of neurological diseases,improve the accuracy of laboratory diagnosis,and optimize clinical treatment strategies,but it may also play an important role in prognostic monitoring.In addition,the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized.This review may contribute to the development of new approaches for the treatment of neurological diseases.

Human-induced pluripotent stem cell-derived neural stem cell exosomes improve blood-brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis

Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

Activation of the wnt/β-catenin/CYP1B1 pathway alleviates oxidative stress and protects the blood-brain barrier under cerebral ischemia/reperfusion conditions

Accumulating evidence suggests that oxidative stress and the Wnt/β-catenin pathway participate in stroke-induced disruption of the blood-brain barrier.However,the potential links between them following ischemic stroke remain largely unknown.The present study found that cerebral ischemia leads to oxidative stress and repression of the Wnt/β-catenin pathway.Meanwhile,Wnt/β-catenin pathway activation by the pharmacological inhibito r,TWS119,relieved oxidative stress,increased the levels of cytochrome P4501B1(CYP1B1)and tight junction-associated proteins(zonula occludens-1[ZO-1],occludin and claudin-5),as well as brain microvascular density in cerebral ischemia rats.Moreove r,rat brain microvascular endothelial cells that underwent oxygen glucose deprivation/reoxygenation displayed intense oxidative stress,suppression of the Wnt/β-catenin pathway,aggravated cell apoptosis,downregulated CYP1B1and tight junction protein levels,and inhibited cell prolife ration and migration.Overexpression ofβ-catenin or knockdown ofβ-catenin and CYP1B1 genes in rat brain mic rovascular endothelial cells at least partly ameliorated or exacerbated these effects,respectively.In addition,small interfering RNA-mediatedβ-catenin silencing decreased CYP1B1 expression,whereas CYP1B1 knoc kdown did not change the levels of glycogen synthase kinase 3β,Wnt-3a,andβ-catenin proteins in rat brain microvascular endothelial cells after oxygen glucose deprivatio n/reoxygenation.Thus,the data suggest that CYP1B1 can be regulated by Wnt/β-catenin signaling,and activation of the Wnt/β-catenin/CYP1B1 pathway contributes to alleviation of oxidative stress,increased tight junction levels,and protection of the blood-brain barrier against ischemia/hypoxia-induced injury.

Blood-brain barrier pathology in cerebral small vessel disease

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly.Although at first it was considered innocuous,small vessel disease is nowadays regarded as one of the major vascular causes of dementia.Radiological signs of small vessel disease include small subcortical infarcts,white matter magnetic resonance imaging hyperintensities,lacunes,enlarged perivascular spaces,cerebral microbleeds,and brain atrophy;however,great heterogeneity in clinical symptoms is observed in small vessel disease patients.The pathophysiology of these lesions has been linked to multiple processes,such as hypoperfusion,defective cerebrovascular reactivity,and blood-brain barrier dysfunction.Notably,studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease.Therefore,the purpose of this review is to provide a new foundation in the study of small vessel disease pathology.First,we discuss the main structural domains and functions of the blood-brain barrier.Secondly,we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease.Finally,we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

Rebuilding insight into the pathophysiology of Alzheimer’s disease through new blood-brain barrier models

The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system.Blood-brain barrier breakdown is a common pathology in various neurological diseases,such as Alzheimer’s disease,stroke,multiple sclerosis,and Parkinson’s disease.Traditionally,it has been considered a consequence of neuroinflammation or neurodegeneration,but recent advanced imaging techniques and detailed studies in animal models show that blood-brain barrier breakdown occurs early in the disease process and may precede neuronal loss.Thus,the blood-brain barrier is attractive as a potential therapeutic target for neurological diseases that lack effective therapeutics.To elucidate the molecular mechanism underlying blood-brain barrier breakdown and translate them into therapeutic strategies for neurological diseases,there is a growing demand for experimental models of human origin that allow for functional assessments.Recently,several human induced pluripotent stem cell-derived blood-brain barrier models have been established and various in vitro blood-brain barrier models using microdevices have been proposed.Especially in the Alzheimer’s disease field,the human evidence for blood-brain barrier dysfunction has been demonstrated and human induced pluripotent stem cell-derived blood-brain barrier models have suggested the putative molecular mechanisms of pathological blood-brain barrier.In this review,we summarize recent evidence of blood-brain barrier dysfunction in Alzheimer’s disease from pathological analyses,imaging studies,animal models,and stem cell sources.Additionally,we discuss the potential future directions for blood-brain barrier research.

Post-acute ischemic stroke hyperglycemia aggravates destruction of the blood-brain barrier

Post-acute ischemic stroke hyperglycemia increases the risk of hemorrhagic transformation,which is associated with blood-brain barrier disruption.Brain microvascular endothelial cells are a major component of the blood-brain barrier.Intercellular mitochondrial transfer has emerged as a novel paradigm for repairing cells with mitochondrial dysfunction.In this study,we first investigated whether mitochondrial transfer exists between brain microvascular endothelial cells,and then investigated the effects of post-acute ischemic stroke hyperglycemia on mitochondrial transfer between brain microvascular endothelial cells.We found that healthy brain microvascular endothelial cells can transfer intact mitochondria to oxygen glucose deprivation-injured brain microvascular endothelial cells.However,post-oxygen glucose deprivation hyperglycemia hindered mitochondrial transfer and exacerbated mitochondrial dysfunction.We established an in vitro brain microvascular endothelial cell model of the blood-brain barrier.We found that post-acute ischemic stroke hyperglycemia reduced the overall energy metabolism levels of brain microvascular endothelial cells and increased permeability of the blood-brain barrier.In a clinical study,we retrospectively analyzed the relationship between post-acute ischemic stroke hyperglycemia and the severity of hemorrhagic transformation.We found that post-acute ischemic stroke hyperglycemia serves as an independent predictor of severe hemorrhagic transformation.These findings suggest that post-acute ischemic stroke hyperglycemia can aggravate disruption of the blood-brain barrier by inhibiting mitochondrial transfer.

Targeting brain tumors with innovative nanocarriers:bridging the gap through the blood-brain barrier

Background:Glioblastoma multiforme(GBM)is recognized as the most lethal and most highly invasive tumor.The high likelihood of treatment failure arises fromthe presence of the blood-brain barrier(BBB)and stemcells around GBM,which avert the entry of chemotherapeutic drugs into the tumormass.Objective:Recently,several researchers have designed novel nanocarrier systems like liposomes,dendrimers,metallic nanoparticles,nanodiamonds,and nanorobot approaches,allowing drugs to infiltrate the BBB more efficiently,opening up innovative avenues to prevail over therapy problems and radiation therapy.Methods:Relevant literature for this manuscript has been collected from a comprehensive and systematic search of databases,for example,PubMed,Science Direct,Google Scholar,and others,using specific keyword combinations,including“glioblastoma,”“brain tumor,”“nanocarriers,”and several others.Conclusion:This review also provides deep insights into recent advancements in nanocarrier-based formulations and technologies for GBM management.Elucidation of various scientific advances in conjunction with encouraging findings concerning the future perspectives and challenges of nanocarriers for effective brain tumor management has also been discussed.

Functionalized lipid nanoparticles modulate the blood-brain barrier and eliminate α-synuclein to repair dopamine neurons

The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.

Association between intercellular adhesion molecule-1 to depression and blood-brain barrier penetration in cerebellar vascular disease

BACKGROUND Cerebral small vessel disease(CSVD)is a prevalent cerebrovascular disease in clinical practice that is often associated with macrovascular disease.A clear understanding of the underlying causes of CSVD remains elusive.AIM To explore the association between intercellular adhesion molecule-1(ICAM-1)and blood-brain barrier(BBB)penetration in CSVD.METHODS This study included patients admitted to Fuyang People’s Hospital and Fuyang Community(Anhui,China)between December 2021 and March 2022.The study population comprised 142 patients,including 80 in the CSVD group and 62 in the control group.Depression was present in 53 out of 80 patients with CSVD.Multisequence magnetic resonance imaging(MRI)and dynamic contrast-enhanced MRI were applied in patients to determine the brain volume,cortical thickness,and cortical area of each brain region.Moreover,neuropsychological tests including the Hamilton depression scale,mini-mental state examination,and Montreal cognitive assessment basic scores were performed.RESULTS The multivariable analysis showed that age[P=0.011;odds ratio(OR)=0.930,95%confidence interval(CI):0.880-0.983]and ICAM-1 levels(P=0.023;OR=1.007,95%CI:1.001-1.013)were associated with CSVD.Two regions of interest(ROIs;ROI3 and ROI4)in the white matter showed significant(both P<0.001;95%CI:0.419-0.837 and 0.366-0.878)differences between the two groups,whereas only ROI1 in the gray matter showed signi-ficant difference(P=0.046;95%CI:0.007-0.680)between the two groups.ICAM-1 was significantly correlated(all P<0.05)with cortical thickness in multiple brain regions in the CSVD group.CONCLUSION This study revealed that ICAM-1 levels were independently associated with CSVD.ICAM-1 may be associated with cortical thickness in the brain,predominantly in the white matter,and a significant increase in BBB permeability,proposing the involvement of ICAM-1 in BBB destruction.

Super Antibiotics, Part II. Hyperforin, Mass Spectroscopy (MS) and Gas Chromatography-Mass Spectrometry (GC-MS), Evidence of Permeability of the Blood-Testis Barrier (BTB) and the Blood-Brain Barrier (BBB) to Hyperforin

In the first article of this series, we presented some evidence of hyperforin as an antibiotic, antiprotozoal, antiviral, anticancer, and immunomodulatory substance. In the present article, evidence of the permeability of the blood-testis barrier (BTB) and blood-brain barrier (BBB) to hyperforin and its distribution in other organs of the domestic pig (Sus scrofa domesticus) are revealed. Seven-month-old male boars with a body mass of 100 kg were fed a diet containing hyperforin. Organs were surgically removed under anesthesia. Organs were suitable prepared and extracted, and then analyzed using gas chromatography-mass spectrometry with supersonic molecular beams (GC-MS with SMB). The presence of hyperforin was recorded in all organs and body fluids. Special attention was paid to the evaluation of the presence of hyperforin in the brain and testes of experimental animals. The presence of hyperforin in the brain and testes of experimental animals was established by GC-MS with SMB. The results are of interest because penicillin and numerous other antibiotics cannot pass through the BTB or BBB if healthy or non-inflamed, which limits their use in patients with meningitis and gonorrhea. The findings are also of interest in cases of penicillin- and multi-antibiotic-resistant bacterial infections.

Multimodal comparison of plasma proteins associated with blood-brain barrier impairment in Alzheimer’s disease

Background:Vascular impairment is one of the major contributors to dementia.We aimed to identify blood biomarkers suggestive of potential impairment of the blood-brain barrier(BBB)in subjects with Alzheimer’s disease(AD).Methods:We used administrative data from the VA Informatics and Computing Infrastructure Resource Center to study both inpatients and outpatients with AD.Plasma samples from healthy control and AD individuals were analyzed using enzyme-linked immunosorbent assay and proteomics approaches to identify differentially expressed proteins.Bioinformatic analysis was applied to explore significantly enriched pathways.Results:In the same cohort of patients with AD,we found twice number of subjects with cerebral amyloid angiopathy in the two-year period after the onset of AD,compared to the number of subjects with cerebral amyloid angiopathy in the two-year period prior to AD onset.Different pathways related to BBB,like cell adhesion,extracellular matrix organization and Wnt signaling,were activated and differentially expressed proteins such as ADAM22,PDGFR-α,DKK-4,Neucrin and RSOP-1 were identified.Moreover,matrix metalloproteinase-9,which is implicated in causing degradation of basal lamina and BBB disruption,was significantly increased in the plasma of AD patients.Conclusions:Alteration of proteins found in AD subjects could provide new insights into biomarkers regulating permeability and BBB integrity.

Effects of Minimally Invasive Puncture and Drainage of Intracranial Hematoma on the Blood-brain Barrier in Patients with Cerebral Hemorrhage

The effects of minimally invasive surgery on the blood-brain barrier （BBB） of 30 patients with cerebral hemorrhage were investigated. Difference of the BBB index and serum MBP concentration were assessed in 15 cases of conservative treatment group and 15 cases of minimally invasive surgery group. The BBB index in minimally invasive surgery group was significantly lower than in conservative treatment group （P〈0.05）, and the BBB index in the two treatment groups was significantly higher than in control group （P〈0.01）. Serum MBP concentration in minimally invasive surgery group was significantly lower than in conservative treatment group （P〈0.05）, and that in the two treatment groups was significantly higher than in control group （P〈0.01）. It was suggested the permeability of BBB in patients with cerebral hemorrhage was increased, and BBB index and serum MBP concentration in patients with cerebral hemorrhage were increased. Minimally invasive surgery can reduce the lesion of cytotoxicity to BBB and cerebral edema.

Emerging roles of astrocytes in blood-brain barrier disruption upon amyloid-beta insults in Alzheimer's disease

Blood-brain barrier disruption occurs in the early stages of Alzheimer’s disease.Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer’s disease progression.Astrocytes are the most abundant glial cells in the central nervous system with important roles in the structural and functional maintenance of the blood-brain barrier.For example,astrocytic cove rage around endothelial cells with perivascular endfeet and secretion of homeostatic soluble factors are two major underlying mechanisms of astrocytic physiological functions.Astrocyte activation is often observed in Alzheimer’s disease patients,with astrocytes expressing a high level of glial fibrillary acid protein detected around amyloid-beta plaque with the elevated phagocytic ability for amyloid-beta.Structural alte rations in Alzheimer’s disease astrocytes including swollen endfeet,somata shrinkage and possess loss contribute to disruption in vascular integrity at capillary and arte rioles levels.In addition,Alzheimer’s disease astrocytes are skewed into proinflammatory and oxidative profiles with increased secretions of vasoactive mediators inducing endothelial junction disruption and immune cell infiltration.In this review,we summarize the findings of existing literature on the relevance of astrocyte alte ration in response to amyloid pathology in the context of blood-brain barrier dysfunction.First,we briefly describe the physiological roles of astrocytes in blood-brain barrier maintenance.Then,we review the clinical evidence of astrocyte pathology in Alzheimer’s disease patients and the preclinical evidence in animal and cellular models.We further discuss the structural changes of blood-brain barrier that correlates with Alzheimer’s disease astrocyte.Finally,we evaluate the roles of soluble factors secreted by Alzheimer’s disease astrocytes,providing potential molecular mechanisms underlying blood-brain barrier modulation.We conclude with a perspective on investigating the therapeutic potential of targeting astrocytes for blood-brain barrier protection in Alzheimer’s disease.

Nanocarriers as a powerful vehicle to overcome blood-brain barrier in treating neurodegenerative diseases: Focus on recent advances

Neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,Huntington disease and amyotrophic lateral sclerosis throw a heavy burden on families and society. Related scientific researches make tardy progress. One reason is that the known pathogeny is just the tip of the iceberg. Another reason is that various physiological barriers,especially blood-brain barrier(BBB),hamper effective therapeutic substances from reaching site of action. Drugs in clinical treatment of neurodegenerative diseases are basically administered orally. And generally speaking,the brain targeting efficiency is pretty low. Nanodelivery technology brings hope for neurodegenerative diseases. The use of nanocarriers encapsulating molecules such as peptides and genomic medicine may enhance drug transport through the BBB in neurodegenerative disease and target relevant regions in the brain for regenerative processes. In this review,we discuss BBB composition and applications of nanocarriers-liposomes,nanoparticles,nanomicelles and new emerging exosomes in neurodegenerative diseases. Furthermore,the disadvantages and the potential neurotoxicity of nanocarriers according pharmacokinetics theory are also discussed.

Intranasal nerve growth factor bypasses the blood-brain barrier and affects spinal cord neurons in spinal cord injury

The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an in-creased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deifcits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells.

Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities.Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure,followed by global cerebral ischemia.Post-subarachnoid hemorrhage ischemia,tissue injuries as well as extravasated blood components and the breakdown products activate microglia,astrocytes and Toll-like receptor 4,and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades.Once blood-brain barrier is disrupted,brain tissues are directly exposed to harmful blood contents and immune cells,which aggravate brain injuries furthermore.Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins.Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage,but the exact mechanisms remain unclear.Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage.This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.

In vitro model of the blood-brain barrier established by co-culture of primary cerebral microvascular endothelial and astrocyte cells

Drugs for the treatment and prevention of nervous system diseases must permeate the bloodbrain barrier to take effect.In vitro models of the blood-brain barrier are therefore important in the investigation of drug permeation mechanisms.However,to date,no unified method has been described for establishing a blood-brain barrier model.Here,we modified an in vitro model of the blood-brain barrier by seeding brain microvascular endothelial cells and astrocytes from newborn rats on a polyester Transwell cell culture membrane with 0.4-μm pores,and conducted transepithelial electrical resistance measurements,leakage tests and assays for specific bloodbrain barrier enzymes.We show that the permeability of our model is as low as that of the bloodbrain barrier in vivo.Our model will be a valuable tool in the study of the mechanisms of action of neuroprotective drugs.

Blood-brain barrier modeling: challenges and perspectives

The blood-brain barrier （BBB） forms a highly selective inter- face between blood and brain. Extensive research efforts have completely changed our view of the BBB in the last years, from a static, impermeable barrier to a dynamic, highly regulated and specific cellular system. The BBB ultrastructurally consists of specialized brain microvascular endothelial cells （BMEC） characterized by low pinocytic activity,

The importance of laminin at the blood-brain barrier

The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components.The mechanistic basis of this barrier is found at multiple levels,including the adherens and tight junction proteins that tightly bind adjacent endothelial cells and the influence of neighboring pericytes,microglia,and astrocyte endfeet.In addition,extracellular matrix components of the vascular basement membrane play a critical role in establishing and maintaining blood-brain barrier integrity,not only by providing an adhesive substrate for blood-brain barrier cells to adhere to,but also by providing guidance cues that strongly influence vascular cell behavior.The extracellular matrix protein laminin is one of the most abundant components of the basement membrane,and several lines of evidence suggest that it plays a key role in directing blood-brain barrier behavior.In this review,we describe the basic structure of laminin and its receptors,the expression patterns of these molecules in central nervous system blood vessels and how they are altered in disease states,and most importantly,how genetic deletion of different laminin isoforms or their receptors reveals the contribution of these molecules to blood-brain barrier function and integrity.Finally,we discuss some of the important unanswered questions in the field and provide a“to-do”list of some of the critical outstanding experiments.

Correlation of vascular endothelial growth factor to permeability of blood-brain barrier and brain edema during high-altitude exposure

BACKGROUND： Many studies have evaluated the role of vascular endothelial growth factor （VEGF） in traumatic brain edema and hemorrhagic brain edema. OBJECTIVE： To observe the effects of VEGF expression on permeability of the blood-brain barrier （BBB） during high-altitude and hypoxia exposure, and to investigate the correlation between VEGF expression and BBB permeability with regard to Evans blue staining and brain edema during high-altitude exposure. DESIGN, TIME AND SETTING： The randomized, controlled, animal study was performed at the Tanggula Etape, Central Laboratory of Chengdu Medical College, and Central Laboratory of General Hospital of Chengdu Military Area Command of Chinese PLA, China, from July 2003 to November 2004. MATERIALS： Quantitative RT-PCR kit （Sigma, USA）, VEGF ELISA kit （Biosource, USA）, and Evans blue （Jingchun, China） were acquired for this study. METHODS： A total of 180 Wistar rats were equally and randomly assigned to 15 groups： low-altitude （500 m）, middle-altitude （2 880 m）, high-altitude （4 200 m）, super-high-altitude （5 000 m）, 1,3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 days of super high-altitude exposure. Wistar rats were exposed to various altitude gradients to establish a hypoxia model. MAIN OUTCOME MEASURES： Brain water content was calculated according to the wet-to-dry weight ratio. BBB permeability to Evans blue was determined by colorimetric method. VEGF mRNA and protein levels in brain tissues were detected using RT-PCR and double-antibody sandwich ELISA. RESULTS： Brain water content, BBB permeability to Evans blue, and VEGF mRNA and protein levels in brain tissues increased with increasing altitude and prolonged exposure to altitude. The greatest increase was determined on day 9 upon ascending 5 000 m. Simultaneously, VEGF expression positively correlated to BBB permeability of Evans blue and brain water content （r = 0.975, 0.917, P〈 0.01）. CONCLUSION： Increased VEGF protein and mRNA expression was responsible for increased BBB permeability, which may be an important mechanism underlying brain edema during high-altitude exposure.