Disruption of the Blood-Brain Barrier During Neuroinflammatory and Neuroinfectious Diseases

Structure and function of the blood-brain barrier

ObjectiveOur objective is to explore whether blood–cerebrospinal fluid (CSF) barrier biomarkers differ in episodic migraine (EM) or chronic migraine (CM) from controls.BackgroundReports of blood–brain barrier and blood–cerebrospinal fluid barrier (BCSFB) disruption in migraine vary. Our hypothesis is that investigation of biomarkers associated with blood, CSF, brain, cell adhesion, and inflammation will help elucidate migraine pathophysiology.MethodsWe recruited 14 control volunteers without headache disorders and 42 individuals with EM or CM as classified using the International Classification of Headache Disorders, 3rd edition, criteria in a cross‐sectional study located at our Pasadena and Stanford headache research centers in California. Blood and lumbar CSF samples were collected once from those diagnosed with CM or those with EM during two states: during a typical migraine, before rescue therapy, with at least 6/10 level of pain (ictal); and when migraine free for at least 48 h (interictal). The average number of headaches per month over the previous year was estimated by those with EM; this enabled comparison of biomarker changes between controls and three headache frequency groups: <2 per month, 2–14 per month, and CM. Blood and CSF biomarkers were determined using antibody‐based methods.ResultsAntimigraine medication was only taken by the EM and CM groups. Compared to controls, the migraine group had significantly higher mean CSF–blood quotients of albumin (Qalb: mean ± standard deviation (SD): 5.6 ± 2.3 vs. 4.1 ± 1.9) and fibrinogen (Qfib mean ± SD: 1615 ± 99.0 vs. 86.1 ± 55.0). Mean CSF but not plasma soluble vascular cell adhesion molecule‐1 (sVCAM‐1) levels were significantly higher in those with more frequent migraine: (4.5 ng/mL ± 1.1 in those with <2 headache days a month; 5.5 ± 1.9 with 2–14 days a month; and 7.1 ± 2.9 in CM), while the Qfib ratio was inversely related to headache frequency. We did not find any difference in individuals with EM or CM from controls for CSF cell count, total protein, matrix metalloproteinase‐9, soluble platelet‐derived growth factor receptor β, tumor necrosis factor‐alpha, interferon‐gamma, interleukin (IL)‐6, IL‐8, IL‐10, or C‐reactive protein.ConclusionsThe higher Qalb and Qfib ratios may indicate that the transport of these blood‐derived proteins is disturbed at the BCSFB in persons with migraine. These changes most likely occur at the choroid plexus epithelium, as there are no signs of typical endothelial barrier disruption. The most striking finding in this hypothesis‐generating study of migraine pathophysiology is that sVCAM‐1 levels in CSF may be a biomarker of higher frequency of migraine and CM. An effect from migraine medications cannot be excluded, but there is no known mechanism to suggest they have a role in altering the CSF biomarkers.

In this work, we describe the fabrication and working of a modular microsystem that recapitulates the functions of the "Neurovascular Unit". The microdevice comprised a vertical stack of a poly(dimethylsiloxane) (PDMS) neural parenchymal chamber separated by a vascular channel via a microporous polycarbonate (PC) membrane. The neural chamber housed a mixture of neurons (~4%), astrocytes (~95%), and microglia (~1%). The vascular channel was lined with a layer of rat brain microvascular endothelial cell line (RBE4). Cellular components in the neural chamber and vascular channel showed viability (>90%). The neural cells fired inhibitory as well as excitatory potentials following 10 days of culture. The endothelial cells showed diluted-acetylated low density lipoprotein (dil-a-LDL) uptake, expressed von Willebrand factor (vWF) and zonula occludens (ZO-1) tight junctions, and showed decreased Alexafluor™-conjugated dextran leakage across their barriers significantly compared with controls (p < 0.05). When the vascular layer was stimulated with TNF-α for 6 h, about 75% of resident microglia and astrocytes on the neural side were activated significantly (p < 0.05 compared to controls) recapitulating tissue-mimetic responses resembling neuroinflammation. The impact of this microsystem lies in the fact that this biomimetic neurovascular platform might not only be harnessed for obtaining mechanistic insights for neurodegenerative disorders, but could also serve as a potential screening tool for central nervous system (CNS) therapeutics in toxicology and neuroinfectious diseases.

Copper is indispensable for development and function of the central nervous system (CNS). This is dramatically illustrated by the severe neuropathological deficits in Menkes disease, an X-linked copper deficiency disorder resulting from mutation of the gene that encodes an essential copper transporting P-type ATPase, ATP7A. Since its discovery over two decades ago, the role of ATP7A in copper transport and homeostasis has been inextricably linked to satisfying systemic and CNS requirements for copper. In this issue of American Journal of Physiology - Cell Physiology, Hodgkinson et al. (2015) describe an important body of work, which for the first time distinguishes the CNS requirement for ATP7A from the CNS requirement for copper.

The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.

Part I: Physiology of brain fluids and blood-brain barrier Chapter 1: Anatomy of Fluid Interfaces that Protect the Microenvironment 1.1. Historical perspective 1.2 Cerebral microenvironment 1.3. Development of the brain-fluid interfaces 1.3.1. Neural tube, ependymal cells and stem cells 1.3.2. Cilated ependymal cells and CSF movement 1.3.3. Choroid plexuses, arachnoid and capillaries 1.4. Extracellular Space and Extracellular Matrix 1.5. Brain-Fluid Interfaces 1.5.1. Anatomy of the cerebral blood vessels 1.5.2. Brain cells interfaces with CSF at ependymal and pia 1.6. Dura, arachnoid and pial layers 1.7. What are sources of energy? Chapter 2: Physiology of the Cerebrospinal and Interstitial Fluids 2.1. Introduction 2.2. Proteins in the CSF 2.3. CSF Pressure Reflects Venous Pressure in the Right Heart 2.4. Formation, Circulation and Absorption of CSF 2.4.1. Formation of CSF by choroid plexuses 2.4.2. Choroid plexus and disease biomarkers in CSF 2.4.3. Absorption of CSF at the arachnoid villi 2.5. Electrolyte balance in the CSF 2.6. Meninges and sites of masses and infection 2.7. Interstitial fluid 2.8. Lyphatic drainage 2.9. Water diffusion, bulk flow if ISH and diffusion tensor imaging 2.10. Neuropeptides and fluid homeostasis 2.11. Aquaporins and water transport in the CNS Chapter 3: Neurovascular Unit 3.1. Early experiments on blood-brain barrier 3.2. The Neurovascular unit and tight junction proteins 3.3. Integrins, selectins and endothelial cell adhesion 3.4. Astrocytes, pericytes and basal lamina 3.5. Movement of substances into and out of brain 3.6. Glucose and amino acid transport 3.7. Proteases and the neurovascular unit 3.8. Matrix metalloproteinases (MMPs) 3.9. A disintegrin and metalloproteinase (ADAM) 3.10. Barrier systems evolved to an endothelial barrier Part II: Metabolism, disorders of brain fluids, and mathematics of transport Chapter 4: Glucose, Amino acid and Lipid Metabolism 4.1. Glucose metabolism 4.2. Amino acid neurotransmitters 4.3. Lipid metabolism 4.4. Eicosanoid metabolism 4.5. Hepatic encephalopathy 4.6. Hypoglycemia 4.7. Hyponatremia, osmotic demyelination and acid balance 4.7.1. Hyponatremia 4.7.2. Hyperglycemia 4.7.3. Acidosis Chapter 5: Disorders of Cerebrospinal Circulation: Idiopathic Intracranial Hypertension (IIH) and Hydrocephalus 5.1. Introduction 5.2. Clinical Features of IIH 5.3. Treatment of IIH 5.4. Hydrocephalus 5.5. Hydrocephalus in children 5.6. Adult-onset hydrocephalus 5.6.1. Obstructive hydrocephalus 5.6.2. Normal-pressure hydrocephalus Chapter 6: Quantification of Cerebral Blood Flow and Blood Brain Barrier Transport by NMR and PET 6.1. Introduction 6.2. Mathematical approach to cerebral blood flow and transport 6.2.1. Cerebral blood flow: Schmidt-Kety approach 6.2.2. Regional blood flow 6.2.3. Transport between blood and brain 6.3 Positron emission tomography (PET) 6.3.1. Single-injection external registration 6.3.2. Patlak graphical BBB method for autoradiography and MRI 6.4 Magnetic resonance imaging and spectroscopy 6.4.1. Multinuclear NMR 6.4.2. Relaxation phenomenon and the rotating frame 6.4.3. 31P-MRS 6.4.4. 13C-MRS 6.4.5. 1H-MRS Part III: Ischemia, edema and inflammation Chapter 7: Mechanisms of Ischemic/Hypoxic Brain Injury 7.1. Epidemiology, risk factors and prevention of stroke 7.2. Molecular cascades in ischemic tissue results from energy failure 7.3. Excitatory and inhibitory neurotransmitters 7.4. Neuroinflammation in stroke 7.5. Proteases in hypoxia/ischemia 7.6. Caspases and cell death 7.7. Tissue inhibitors of metalloproteinases (TIMPs) and apoptosis 7.8. Tight junction proteins and MMPs 7.9. MMPs and tPA-induced bleeding 7.10. Animal models in stroke 7.11. Arteriovenous malformations and cavernous hemangiomas 7.12. MRI, PET and EPR in hypoxia-ischemia 7.12.1. MRI and MRS 7.12.2. Positron emission tomography (PET) 7.12.3. Electron paramagnetic resonance Chapter 8: Vascular Cognitive Impairment and Alzheimer's Disease 8.1. Regulation of cerebral blood flow 8.2. Hypoxia-ischemia in cardiac arrest 8.2.1 Prognosis for recovery after cardiac arrest 8.2.2 Cardiac surgery and memory loss 8.2.3 Delayed post anoxic leukoencephalopathy 8.3. Hypoxia inducible factors and gene expression 8.4. Intermittent hypoxia is a strong stimulus for HIF 8.5. Vascular cognitive impairment 8.6. White matter hyperintensities on MRI and Binswanger's disease 8.7. Alzheimer's disease, vascular disease and the amyloid hypothesis Chapter 9: Effects of Altitude on the Brain 9.1. Introduction 9.2. Genetic tolerance to altitude 9.3. Acute mountain sickness and high altitude pulmonary edema 9.4. High altitude cerebral edema 9.5. Cognitive consequences of hypobaric hypoxia 9.6. Imaging of the brain at high altitude 9.7. Hypoxia-inducible factors and sleep disorders in AMS 9.8. Treatment of altitude illnesses Chapter 10: Brain Edema 10.1. Introduction 10.2. Role of aquaporins in brain edema 10.3. Role of Neuroinflammation in the formation of vasogenic edema 10.3.1. Oxidative stress and brain edema 10.3.2 . Arachidonic acid and brain edema 10.3.3. Vascular endothelial growth factor and angiopoietins 10.4. Clinical conditions associated with brain edema 10.5. Imaging brain edema 10.6 . Treatment of brain edema and hypoxic/ischemic injury 10.7. Multiple drugs for treatment of ischemia Chapter 11: Intracerebral Hemorrhage 11.1. Introduction 11.2. History of ICH 11.3. Molecular mechanisms in ICH 11.4. Clinical aspects of intracranial bleeding 11.5. Pathophysiology of ICH: Evidence from animal studies 11.6 Extrapolation of experimental results to treatments for ICH Chapter 12: Autoimmunity, Hypoxia, and Inflammation in Demyelinating Diseases 12.1. Introduction 12.2. Heterogeneity of the pathological findings in MS 12.3. Proteases implicated in MS pathology 12.4. BBB disruption in MS 12.5. Devic's neuromyelitis optica 12.6. Nonimmunological processes in demyelination 12.7. Experimental allergic encephalomyelitis and pathogenesis of MS 12.8. Epilogue- synthesis and future directions

The Neuroinfectious diseases profile in a specialist neurology centre in South Africa

Restorative strategies after stroke are focused on the remodeling of cerebral endothelial cells and brain parenchymal cells. The latter, i.e., neurons, neural precursor cells and glial cells, synergistically interact with endothelial cells in the ischemic brain, providing a neurovascular unit (NVU) remodeling that can be used as target for stroke therapies. Intercellular communication and signaling within the NVU, the multicellular brain-vessel-blood interface, including its highly selective blood-brain barrier, are fundamental to the central nervous system homeostasis and function. Emerging research designates cell-derived extracellular vesicles and especially the nano-sized exosomes, as a complex mean of cell-to-cell communication, with potential use for clinical applications. Through their richness in active molecules and biological information (e.g., proteins, lipids, genetic material), exosomes contribute to intercellular signaling, a condition particularly required in the central nervous system. Cerebral endothelial cells, perivascular astrocytes, pericytes, microglia and neurons, all part of the NVU, have been shown to release and uptake exosomes. Also, exosomes cross the blood-brain and blood-cerebrospinal fluid barriers, allowing communication between periphery and brain, in normal and disease conditions. As such exosomes might be a powerful diagnostic tool and a promising therapeutic shuttle of natural nanoparticles, but also a means of disease spreading (e.g., immune system modulation, pro-inflammatory action, propagation of neurodegenerative factors). This review highlights the importance of exosomes in mediating the intercellular crosstalk within the NVU and reveals the restorative therapeutic potential of exosomes harvested from multipotent mesenchymal stem cells in ischemic stroke, a frequent neurologic condition lacking an efficient therapy.

Inhibition of nitric oxide synthase partially attenuates alterations in the blood-cerebrospinal fluid barrier during experimental meningitis in the rat

ARTICLESPermeability of the choroid plexus of the rabbit to several solutesK Welch, and K SadlerK Welch, and K SadlerPublished Online:01 Mar 1966https://doi.org/10.1152/ajplegacy.1966.210.3.652MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByThe Choroid Plexus and Cerebrospinal Fluid System: Roles in Neurodegenerative DiseasesIn Vitro Models of the Blood–Cerebrospinal Fluid Barrier and Their Use in Neurotoxicological Research14 February 2011The Blood–Cerebrospinal Fluid Barrier: Structure and Functional Significance12 November 2010Les plexus choroïdes : une interface dynamique entre sang et liquide cephalo-rachidienMorphologie, Vol. 89, No. 285In Vitro Investigation of the Blood‚ÄìCerebrospinal Fluid Barrier Properties14 January 2010Choroid plexus controls brain availability of anti-HIV nucleoside analogs via pharmacologically inhibitable organic anion transportersAIDS, Vol. 17, No. 10The transport of the anti-HIV drug, 2′,3′-didehydro-3′-deoxythymidine (D4T), across the blood-brain and blood-cerebrospinal fluid barriers3 February 2009 | British Journal of Pharmacology, Vol. 125, No. 1Electrolyte TransportIntroductionMethods for the study of the functions of the blood-brain barrierBlood-cerebrospinal fluid barrier alteration following intraventricularly administered cholera toxinBrain Research, Vol. 419, No. 1-2Cerebrovascular Permeability Coefficients to Sodium, Potassium, and Chloride5 October 2006 | Journal of Neurochemistry, Vol. 46, No. 6Permeability of epidural somatostatin and morphine into the intrathecal space of dogsRegulatory Peptides, Vol. 13, No. 2Permeability of the blood-cerebrospinal fluid and blood-brain barriers to thyrotropin-releasing hormoneBrain Research, Vol. 358, No. 1-2Cerebrospinal fluid and extracellular fluid: their relationship to pressure and duration of canine hydrocephalusChild's Nervous System, Vol. 1, No. 1Capillary permeability in the isolated rabbit heart as measured by local tissue clearanceMicrovascular Research, Vol. 27, No. 2Recent research into the nature of cerebrospinal fluid formation and absorptionJournal of Neurosurgery, Vol. 59, No. 3Peptides and the blood-brain barrierLife Sciences, Vol. 32, No. 23Uptake of 36 Cl and 22 Na by the Brain-Cerebrospinal Fluid System: Comparison of the Permeability of the Blood-Brain and Blood-Cerebrospinal Fluid BarriersJournal of Neurochemistry, Vol. 37, No. 1Methods for quantifying the transport of drugs across brain barrier systemsPharmacology & Therapeutics, Vol. 14, No. 2Structural Aspects of Brain Barriers, with Special Reference to the Permeability of the Cerebral Endothelium and Choroidal EpitheliumMicroperoxidase uptake into the rat choroid plexus epitheliumJournal of Ultrastructure Research, Vol. 62, No. 2Role of Tight Junctions in Epithelial FunctionFine structure of tight junctions between rat choroidal cells after osmotic opening induced by urea and sucroseTissue and Cell, Vol. 10, No. 2The secretion of cerebrospinal fluidExperimental Eye Research, Vol. 25Choroid plexus absorption of horseradish peroxidase from the cerebral ventriclesJournal of Ultrastructure Research, Vol. 55, No. 3FEATURES OF THE CHOROID PLEXUS OF THE CAT, STUDIED IN VITRO**Supported by Research Grant RO1-NS-09948, National Institute of Neurological Diseases and Stroke.Histochemistry of Choroid PlexusPhysiology of the Choroid PlexusRoutes of nonelectrolyte permeation across epithelial membranesThe Journal of Membrane Biology, Vol. 17, No. 1Untersuchung des an Ventrikelkathetern hydrozephaler Patienten haftenden Gewebes im Licht- und Elektronenmikroskop1 September 1974 | Acta Neurochirurgica, Vol. 30, No. 3-4In vitro studies on the uptake and incorporation of natural amino acids in rabbit choroid plexusBrain Research, Vol. 73, No. 1The movement of lanthanum across diffusion barriers in the choroid plexus of the catBrain Research, Vol. 67, No. 1Stereospecific Permeability of Rat Blood-Brain Barrier to Lactic AcidStroke, Vol. 5, No. 1Accumulation and transport of amino acids by the frog choroid plexusBrain Research, Vol. 44, No. 1Vergleichende untersuchungenüber die substratoxydation durch den plexus chorioideus und hirnrindenschnitte des kaninchensin vitroBrain Research, Vol. 39, No. 2Die Bedeutung von Plasmakreatin und neurologischen Erkrankungen f�r den Kreatingehalt im Liquor cerebrospinalis beim MenschenZeitschrift f�r Neurologie, Vol. 201, No. 4The Blood–Brain BarrierDiffusion coefficients of some 14C-labeled saccharides of biological interestLife Sciences, Vol. 10, No. 14Cerebrospinal fluid production rates determined by simultaneous albumin and inulin perfusionExperimental Neurology, Vol. 29, No. 3Variations in protein permeability in different regions of the cerebrospinal fluidExperimental Neurology, Vol. 28, No. 2Cooperative phenomena in the permeation of sugars through the lining epithelium of choroid plexusBrain Research, Vol. 19, No. 3Diffusion of radioactive nonelectrolytes in saline-agar gelsAnalytical Biochemistry, Vol. 27, No. 3Choroid PlexusChoroid PlexusDie sph�rischen Lipidk�rper im Epithel des Plexus chorioideus beim KaninchenZeitschrift f�r Zellforschung und Mikroskopische Anatomie, Vol. 100, No. 2The Intracerebral Movement of Proteins Injected into Blood and Cerebrospinal Fluid of MiceElectrical Potentials of Choroid Plexus of the RabbitJournal of Neurosurgery, Vol. 22, No. 4 More from this issue > Volume 210Issue 3March 1966Pages 652-660 Copyright & PermissionsCopyright © 1966 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1966.210.3.652PubMed5933221History Published online 1 March 1966 Published in print 1 March 1966 Metrics

Subtle blood-brain barrier (BBB) disruption is involved in numerous neurological conditions. This disruption is found diffusely in the brain and requires quantitative methods for assessment. We propose a statistical method to identify individual voxels where the BBB is disrupted using T1-weighted MRI. We used models of severe and focal vs. mild and generalized disruption of the BBB to show proof of principle with the cold injury model, hypoxia, and a model of inflammation using low- and high-dose lipopolysaccharide (LPS) treatment. Using voxel-based analysis, we found that mild hypoxia resulted in diffuse disruption of the BBB, whereas more severe hypoxia and high-dose LPS treatment resulted in prominent leakage, particularly in the periventricular area, suggestive of blood-cerebrospinal fluid (CSF) barrier disruption. Our data suggest that the periventricular area may be compromised first in conditions of inflammation and hypoxia. Voxel-based analysis could be used in future studies assessing subtle blood-CSF or BBB disruption.

Exchange of albumin between blood, cerebrospinal fluid, and brain in the cat.

IntroductionThe neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU.MethodWe used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries.ResultsThis system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer’s disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model.ConclusionThis model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.

Mediators of Inflammation as Targets for Chronic Pain Treatment

This editorial discusses advances in brain barrier and brain fluid research in 2020. Topics include: the cerebral endothelium and the neurovascular unit; the choroid plexus; the meninges; cerebrospinal fluid and the glymphatic system; disease states impacting the brain barriers and brain fluids; drug delivery to the brain. This editorial also highlights the recently completed Fluids Barriers CNS thematic series entitled, ‘Advances in in vitro modeling of the blood–brain barrier and neurovascular unit’. Such in vitro modeling is progressing rapidly.