Chronic Inflammatory Pain and the Neurovascular Unit: A Central Role for Glia in Maintaining BBB Integrity?

Willis, Colin L.; Davis, Thomas P.

doi:10.2174/138161208784705414

Cited by 53 publications

(54 citation statements)

References 230 publications

(287 reference statements)

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“…The biological rationale for co-culturing astrocytes with endothelial cells is that the astrocytes are affected by substances released from the capillary endothelial cells of the BBB (31). These interactions are essential for a functional neurovascular unit (4,32). The endothelial cells are not directly in physical contact with the astrocytes, and interaction in the model is brought about through the shared medium.…”

Section: Methodsmentioning

confidence: 99%

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

Forshammar

Block

Lundborg

et al. 2011

Journal of Biological Chemistry

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Infection, tissue damage, or other conditions can lead to a neuroinflammatory state. Lipopolysaccharide (LPS) exposure can be used experimentally as a model to generate an inflammatory response both in vitro and in vivo. Endotoxin, or LPS, is a potent inflammatory activator (1) in astrocytes and microglia, with stimulation of Toll-like receptor 4 (TLR4) (2). The expression of TLR4 is up-regulated in astrocytes under neuroinflammatory conditions (3). Activation of TLR4 leads to activation of nuclear factor-B, a factor that regulates expression of genes involved in immune responses, including release of the proinflammatory cytokines tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) (2).Astrocytes in networks, positioned between the vasculature and synapses, monitor neuronal signaling, including rebuilding of synapses (4, 5). Astrocytes express almost the same repertoire of receptors and ion channels as neurons. They regulate synaptic transmission via a bidirectional communication with neurons, and they release gliotransmitters as well as factors, including cytokines, fatty acid metabolites, and free radicals (6 -8).The Ca 2ϩ signaling in astrocytes over long distances is analogous to, but much slower than, the propagation of action potentials in neurons (9). These astrocytic Ca 2ϩ waves (10, 11) can be evoked by transmitters released from neurons and glial cells, followed by activation of especially G protein-coupled receptors. Cytosolic Ca 2ϩ plays a key role as a second messenger, and the control of Ca 2ϩ signals is therefore critical. This involves coordination of Ca 2ϩ entry across the plasma membrane (PM), 2 Ca 2ϩ release from the endoplasmatic reticulum (ER), refilling of the ER stores, and extrusion across the PM (12). The Na ϩ -Ca 2ϩ exchanger, a Ca 2ϩ transporter that controls the intracellular Ca 2ϩ concentrations, is driven by the Na ϩ electrochemical gradient across the PM. This Na ϩ pump, Na ϩ /K ϩ -ATPase, indirectly modulates Ca 2ϩ signaling (13), and inflammatory stimuli influence Ca 2ϩ homeostasis in the astrocyte networks (5, 14 -16).The cytoskeleton seems to be important in this system for controlling of PM microdomains and the ER complex. The adaptor protein ankyrin B is associated with the Na ϩ pump and also with ER proteins, such as the inositol 1,4,5-trisphosphate (IP 3 ) receptor. The main cytoplasmic matrix of proteins, spectrin and actin, are attached to ankyrin B. An intact cytoskeleton is required for the propagation of astrocytic Ca 2ϩ waves (17)

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Section: Methodsmentioning

confidence: 99%

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

Forshammar

Block

Lundborg

et al. 2011

Journal of Biological Chemistry

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“…Toll-like receptors on astrocytes and microglia are considered profound contributors to chronic pain. Figure modified from original (Willis and Davis 2008). Reprinted with permission from Bentham Science Publishers Ltd. 182 WILLIS TOXICOLOGIC PATHOLOGY be attenuated by ibudilast through its glial modulation properties and altered cytokine levels.…”

Section: Pharmacological Modulation Of Glia For the Therapy Of Diseasementioning

confidence: 99%

“…Other components of the neurovascular unit are neurons, pericytes located in the basal lamina, and microglia. Figures reprinted with permission from Bentham Science Publishers Ltd. (Willis and Davis 2008). Vol.…”

Section: Introductionmentioning

confidence: 99%

Glia-Induced Reversible Disruption of Blood–Brain Barrier Integrity and Neuropathological Response of the Neurovascular Unit

Willis

2010

Toxicol Pathol

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The blood-brain barrier (BBB) is the regulated interface that mediates selective transcellular transport of nutrients and essential components from the blood into the brain parenchyma. Many neurodegenerative diseases including stroke, multiple sclerosis, rheumatoid arthritis, and AIDS dementia exhibit loss of BBB integrity. Despite the increasing body of evidence for the involvement of glia in maintaining the BBB, few studies have addressed glial/endothelial/extracellular matrix interactions. A chemically induced astrocyte lesion provides a noninvasive model to study reversible BBB dysfunction in vivo. Blood-brain barrier integrity was assessed with fluorescent dextran tracers (3-70 kDa) and magnetic resonance imaging, in parallel with confocal and electron microscopy imaging of the neurovascular unit. These studies demonstrated modified tight-junction protein expression with loss of vascular integrity. We propose that adherens junction proteins and extracellular matrix remodeling provide a temporary size-selective barrier, whereas astrocyte and microglia activation direct tight-junction proteins to paracellular domains and restore BBB integrity. Morphological comparisons were made with the area postrema, a circumventricular organ with a naturally porous BBB. Further studies into cellular mechanisms of glial/endothelial/extracellular matrix interactions may identify novel glial-based therapeutic targets and innovate therapies for modulating diseases in which gliosis and raised levels of pro-inflammatory mediators are central components.

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“…In health, the BBB acts as a crucial homeostatic regulator for promoting neuronal survival and restricts peripherally circulating toxins, blood proteins, and micro-organisms from entering brain tissue (Abbott et al, 2010;Banks and Erickson, 2010). The low permeability of the BBB is due, in part, to tight junction complexes composed of various transmembrane proteins, including claudin, occludin, and junctional adhesion molecule subfamilies (Tsukita et al, 2001;Chiba et al, 2008;Willis et al, 2008Willis et al, , 2010. The integrity of the BBB is compromised in many central nervous system disorders, including demyelinating disorders, such as multiple sclerosis and in cerebral ischemia (Grossman et al, 1986;Hatashita and Hoff, 1990;Lo et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Biphasic Modulation of Paracellular Claudin-5 Expression in Mouse Brain Endothelial Cells Is Mediated through the Phosphoinositide-3-Kinase/AKT Pathway

Camire

Beaulac

Brule

et al. 2014

J Pharmacol Exp Ther

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Blood-brain barrier (BBB) integrity is compromised in many central nervous system disorders. Complex astrocyte and vascular endothelial cell interactions that regulate BBB integrity may be disturbed in these disorders. We previously showed that systemic administration of 3-chloropropanediol [(S)-(1)-3-chloro-1,2-propanediol] induces a transitory glial fibrillary acidic proteinastrocyte loss, reversible loss of tight junction complexes, and BBB integrity disruption. However, the intracellular signaling mechanisms that induce BBB integrity marker loss are unclear. We hypothesize that 3-chloropropanediol-induced modulation of tight junction protein expression is mediated through the phosphoinositide-3-kinase (PI3K)/AKT pathway. To test this hypothesis, we used a mouse brain endothelial cell line (bEnd.3) exposed to 3-chloropropanediol for up to 3 days. Results showed early reversible loss of sharp paracellular claudin-5 expression 90, 105, and 120 minutes after 3-chloropropanediol (500 mM) treatment. Sharp paracellular claudin-5 profiles were later restored, but lost again by 2 and 3 days after 3-chloropropanediol treatment. Western blot and immunofluorescence studies showed increased p85-PI3K expression and transitory increased AKT (Thr308) phosphorylation at 15 and 30 minutes after 3-chloropropanediol administration. PI3K inhibitors LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride; 2.5-25 mM] and PI-828 [2-(4-morpholinyl)-8-(4-aminopheny)l-4H-1-benzopyran-4-one; 0.1-10 mM] prevented the 3-chloropropanediol-induced AKT (Thr308) phosphorylation and both early and late loss of paracellular claudin-5. However, AKT inhibitors only prevented the early changes in claudin-5 expression. This mechanistic study provides a greater understanding of the intracellular signaling pathways mediating tight junction protein expression and supports a hypothesis that two independent pathways triggered by PI3K mediate early and late loss of paracellular claudin-5 expression.

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Chronic Inflammatory Pain and the Neurovascular Unit: A Central Role for Glia in Maintaining BBB Integrity?

Cited by 53 publications

References 230 publications

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

Glia-Induced Reversible Disruption of Blood–Brain Barrier Integrity and Neuropathological Response of the Neurovascular Unit

Biphasic Modulation of Paracellular Claudin-5 Expression in Mouse Brain Endothelial Cells Is Mediated through the Phosphoinositide-3-Kinase/AKT Pathway

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