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Journal ArticleDOI

The blood-spinal cord barrier: morphology and clinical implications.

TL;DR: This review summarizes current knowledge of the morphology of the BSCB, the methodology of studying the B SCB, and the potential role of BSCBs dysfunction in selected disorders of the spinal cord, and finally summarizes therapeutic approaches to the BscB.
Abstract: The blood-spinal cord barrier (BSCB) is the functional equivalent of the blood-brain barrier (BBB) in the sense of providing a specialized microenvironment for the cellular constituents of the spinal cord. Even if intuitively the BSCB could be considered as the morphological extension of the BBB into the spinal cord, evidence suggests that this is not so. The BSCB shares the same principal building blocks with the BBB; nevertheless, it seems that morphological and functional differences may exist between them. Dysfunction of the BSCB plays a fundamental role in the etiology or progression of several pathological conditions of the spinal cord, such as spinal cord injury, amyotrophic lateral sclerosis, and radiation-induced myelopathy. This review summarizes current knowledge of the morphology of the BSCB, the methodology of studying the BSCB, and the potential role of BSCB dysfunction in selected disorders of the spinal cord, and finally summarizes therapeutic approaches to the BSCB.
Citations
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Journal ArticleDOI
TL;DR: This review discusses the cellular and molecular composition of the blood–brain barrier and how the development and function of the BBB is regulated by interactions with the CNS microenvironment.
Abstract: The blood-brain barrier (BBB) is a term used to describe a series of properties possessed by the vasculature of the central nervous system (CNS) that tightly regulate the movement of ions, molecules, and cells between the blood and the CNS. This barrier is crucial to provide the appropriate environment to allow for proper neural function, as well as protect the CNS from injury and disease. In this review, I discuss the cellular and molecular composition of the BBB and how the development and function of the BBB is regulated by interactions with the CNS microenvironment. I further discuss what is known about BBB dysfunction during CNS injury and disease, as well as methodology used to deliver drugs across the BBB to the CNS.

464 citations

Journal ArticleDOI
TL;DR: The perineuronal net and how chondroitin sulfate proteoglycans deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone are discussed.
Abstract: Since no approved therapies to restore mobility and sensation following spinal cord injury (SCI) currently exist, a better understanding of the cellular and molecular mechanisms following SCI that compromise regeneration or neuroplasticity is needed to develop new strategies to promote axonal regrowth and restore function. Physical trauma to the spinal cord results in vascular disruption that, in turn, causes blood-spinal cord barrier rupture leading to hemorrhage and ischemia, followed by rampant local cell death. As subsequent edema and inflammation occur, neuronal and glial necrosis and apoptosis spread well beyond the initial site of impact, ultimately resolving into a cavity surrounded by glial/fibrotic scarring. The glial scar, which stabilizes the spread of secondary injury, also acts as a chronic, physical, and chemo-entrapping barrier that prevents axonal regeneration. Understanding the formative events in glial scarring helps guide strategies towards the development of potential therapies to enhance axon regeneration and functional recovery at both acute and chronic stages following SCI. This review will also discuss the perineuronal net and how chondroitin sulfate proteoglycans (CSPGs) deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone. We will end the review with a summary of current CSPG-targeting strategies that help to foster axonal regeneration, neuroplasticity/sprouting, and functional recovery following SCI.

461 citations

Journal ArticleDOI
TL;DR: Despite rapid progress, randomised clinical trials to test new drugs will be challenging because of the small number of individuals with the disorder, and new drug candidates have emerged, such as aquaporumab (non-pathogenic antibody blocker of AQP4-IgG binding), sivelestat (neutrophil elastase inhibitor), and eculizumab(complement inhibitor).
Abstract: Summary Neuromyelitis optica is an inflammatory demyelinating disorder of the CNS. The discovery of circulating IgG1 antibodies against the astrocyte water channel protein aquaporin 4 (AQP4) and the evidence that AQP4-IgG is involved in the development of neuromyelitis optica revolutionised our understanding of the disease. However, important unanswered questions remain—for example, we do not know the cause of AQP4-IgG-negative disease, how astrocyte damage causes demyelination, the role of T cells, why peripheral AQP4-expressing organs are undamaged, and how circulating AQP4-IgG enters neuromyelitis optica lesions. New drug candidates have emerged, such as aquaporumab (non-pathogenic antibody blocker of AQP4-IgG binding), sivelestat (neutrophil elastase inhibitor), and eculizumab (complement inhibitor). Despite rapid progress, randomised clinical trials to test new drugs will be challenging because of the small number of individuals with the disorder.

455 citations

Journal ArticleDOI
TL;DR: There has been a recent revival of interest in the use of antisense oligonucleotides to treat several neurodegenerative disorders using different approaches to prevent disease onset or halt disease progression and the first clinical trials for spinal muscular atrophy and amyotrophic lateral sclerosis showing promising results.

249 citations

Journal ArticleDOI
TL;DR: The knowledge of all of these mechanisms might ultimately lead to the invention of drugs to control barrier function to help ameliorating or curing neurological diseases.
Abstract: The peripheral (PNS) and central nervous system (CNS) are delicate structures, highly sensitive to homeostatic changes-and crucial for basic vital functions. Thus, a selection of barriers ensures the protection of the nervous system from noxious blood-borne or surrounding stimuli. In this chapter, anatomy and functioning of the blood-nerve (BNB), the blood-brain (BBB), and the blood-spinal cord barriers (BSCB) are presented and the key tight junction (TJ) proteins described: claudin-1, claudin-3, claudin-5, claudin-11, claudin-12, claudin-19, occludin, Zona occludens-1 (ZO-1), and tricellulin are by now identified as relevant for nerval barriers. Different diseases can lead to or be accompanied by neural barrier disruption, and impairment of these barriers worsens pathology. Peripheral nerve injury and inflammatory polyneuropathy cause an increased permeability of BNB as well as BSCB, while, e.g., diseases of the CNS such as amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury, or Alzheimer's disease can progress and worsen through barrier dysfunction. Moreover, the complex role and regulation of the BBB after ischemic stroke is described. On the other side, PNS and CNS barriers hamper the delivery of drugs in diseases when the barrier is intact, e.g., in certain neurodegenerative diseases or inflammatory pain. Understanding of the barrier - regulating processes has already lead to the discovery of new molecules as drug enhancers. In summary, the knowledge of all of these mechanisms might ultimately lead to the invention of drugs to control barrier function to help ameliorating or curing neurological diseases.

197 citations


Cites background from "The blood-spinal cord barrier: morp..."

  • ...Compared with the BBB, it is more permeable for tracers [86] and cytokines [81], partly due to a relative decrease in occludin and ZO-1 [6]....

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  • ...Damage to the vasculature and breakdown of the BSCB is a universal consequence of spinal cord injury (SCI), clinically as well as in animal models [6]....

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  • ...Its center contains the gray matter, neuronal perikarya, while the surrounding white matter consists of axons (reviewed in [6])....

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References
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Journal ArticleDOI
TL;DR: Specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood–brain barrier function are explored to lead to the development of new protective and restorative therapies.
Abstract: The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.

4,578 citations


"The blood-spinal cord barrier: morp..." refers background in this paper

  • ...For a more detailed description of tight junction proteins, we refer the reader to specialized reviews.(4,6,7)...

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  • ...It seems that the basal lamina is generated and maintained by all the cellular components of the blood– brain interface: endothelial cells, pericytes, and astrocytes.7,8 It has been shown that the basal lamina contributes to the cytoskeletal morphology of brain capillary endothelium, which in turn affects tight junction proteins and the integrity of BBB.7...

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  • ...In 1 of the first in vitro models of BBB, the combined use of morphological and electrophysiological studies revealed the potential of this model for drug delivery across the BBB.31 Numerous other studies further contributed to elucidate histological changes to the BBB and BSBC in in vitro models of BBB.30,32–40 More recent publications have summarized the gain in knowledge and provide the most current insight.41–50 Using immunohistochemical and immunofluorescence technique and fluorescent live imaging, Zehendner et al, demonstrated the role of tight junction proteins, such ad ZO-1 and CL-5, in physiological properties of BBB.51 The interaction between astrocytes and the endothelial cells of the neurovascular unit is crucial for the maintenance of the barrier function....

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  • ...Rather than contributing to the physical properties of the BBB, astrocyte control over the BBB phenotype is exerted mostly via secretory mechanisms that in turn determine the properties of other cellular constituents of the BBB.(6,9) Besides the aforementioned inductive role of astrocytes, astrocytic end feet processes express a high concentration of the water channel aquaporin 4 and potassium channel Kir4....

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  • ...Rather than contributing to the physical properties of the BBB, astrocyte control over the BBB phenotype is exerted mostly via secretory mechanisms that in turn determine the properties of other cellular constituents of the BBB.6,9 Besides the aforementioned inductive role of astrocytes, astrocytic end feet processes express a high concentration of the water channel aquaporin 4 and potassium channel Kir4....

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Journal ArticleDOI
TL;DR: The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms are described.

3,783 citations


"The blood-spinal cord barrier: morp..." refers background in this paper

  • ...between individual endothelial cells.(5) Several plasma membrane proteins forming tight junctions have been identified, including claudin, occludin, and adherens junction molecule....

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Journal ArticleDOI
TL;DR: A standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast‐enhanced T1‐weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd‐DTPA), are described.
Abstract: We describe a standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast-enhanced T(1)-weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd-DTPA). These include a) the volume transfer constant K(trans) (min(-1)); b) the volume of extravascular extracellular space (EES) per unit volume of tissue v(e) (0 < v(e) < 1); and c) the flux rate constant between EES and plasma k(ep) (min(-1)). The rate constant is the ratio of the transfer constant to the EES (k(ep) = K(trans)/v(e)). Under flow-limited conditions K(trans) equals the blood plasma flow per unit volume of tissue; under permeability-limited conditions K(trans) equals the permeability surface area product per unit volume of tissue. We relate these quantities to previously published work from our groups; our future publications will refer to these standardized terms, and we propose that these be adopted as international standards.

3,078 citations


"The blood-spinal cord barrier: morp..." refers background in this paper

  • ...DCE-MRI involves the acquisition of T1weighted magnetic resonance images following intravenous administration of paramagnetic contrast agents such as gadopentetate dimeglumine (Gd).(28) Because the BSCB is impermeable to large molecules such as Gd, which has a molecular weight of 938Da, it can only leak from systemic circulation and into the spinal cord parenchyma when the BSCB is compromised....

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Journal ArticleDOI
24 Jan 2008-Neuron
TL;DR: These findings support developments of new therapeutic approaches for chronic neurodegenerative disorders directed at the blood-brain barrier and other nonneuronal cells of the neurovascular unit.

2,797 citations

Journal ArticleDOI
TL;DR: Understanding how BBB TJ might be affected by various factors holds significant promise for the prevention and treatment of neurological diseases.
Abstract: The blood-brain barrier (BBB) is the regulated interface between the peripheral circulation and the central nervous system (CNS). Although originally observed by Paul Ehrlich in 1885, the nature of the BBB was debated well into the 20th century. The anatomical substrate of the BBB is the cerebral microvascular endothelium, which, together with astrocytes, pericytes, neurons, and the extracellular matrix, constitute a "neurovascular unit" that is essential for the health and function of the CNS. Tight junctions (TJ) between endothelial cells of the BBB restrict paracellular diffusion of water-soluble substances from blood to brain. The TJ is an intricate complex of transmembrane (junctional adhesion molecule-1, occludin, and claudins) and cytoplasmic (zonula occludens-1 and -2, cingulin, AF-6, and 7H6) proteins linked to the actin cytoskeleton. The expression and subcellular localization of TJ proteins are modulated by several intrinsic signaling pathways, including those involving calcium, phosphorylation, and G-proteins. Disruption of BBB TJ by disease or drugs can lead to impaired BBB function and thus compromise the CNS. Therefore, understanding how BBB TJ might be affected by various factors holds significant promise for the prevention and treatment of neurological diseases.

2,374 citations