Neurocan Is Upregulated in Injured Brain and in Cytokine-Treated Astrocytes

Asher, Richard; Morgenstern, Daniel A.; Fidler, Penny S.; Adcock, Kathryn H.; Oohira, Atsuhiko; Braistead, Janet E.; Levine, Joel M.; Margolis, Richard U.; Rogers, J. H.; Fawcett, James W.

doi:10.1523/jneurosci.20-07-02427.2000

Cited by 447 publications

(432 citation statements)

References 65 publications

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“…In opposition to these factors, we previously identified L1-CAM to inhibit NGF mediate sprouting or regeneration of these axons (Romero et al, 2001;Chauhdry et al, 2006), most likely through interactions with the semaphorin 3A receptor complex (Castellani et al, 2000;Chaudhry et al, 2006). Likewise, previous studies have show TGF-␤1 to be a key inducer of chondroitin sulfate proteoglycans by astrocytes (Asher et al, 2000;Smith and Strutz, 2005) and, thus, increases the general axonal growth inhibitory nature of the pathway (Snow et al, 1990;McKeon et al, 1991). Both of these factors showed dramatically less axon growth from DRG transplants than LacZ controls and acted as negative regulators of axon growth along the pathway.…”

Section: Discussionmentioning

confidence: 93%

Targeting Axon Growth from Neuronal Transplants along Preformed Guidance Pathways in the Adult CNS

Ziemba¹,

Chaudhry²,

Rabchevsky³

et al. 2008

J. Neurosci.

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To re-establish neuronal circuits lost after CNS injury, transplanted neurons must be able to extend axons toward their appropriate targets. Such growth is highly restricted within the adult CNS attributable to the expression of inhibitory molecules and general lack of guidance cues to direct axon growth. This environment typically induces random patterns of growth and aberrant innervation, if growth occurs at all. To target the growth of axons from neuronal transplants, we are using viral vectors to create guidance pathways before neuronal transplantation. In this study, we transplanted postnatal rat dorsal root ganglia neurons into the corpus callosum of adult rats. Replication-incompetent adenoviruses encoding growth or guidance factors were injected along the desired pathway 1 week before cell transplantation, allowing time for sufficient protein expression by host glial cells. With expression of nerve growth factor (NGF) and basic fibroblast growth factor, sensory axons were able to grow along the corpus callosum, across the midline, and toward an NGF-expressing target in either the contralateral striatum or cortex: a distance of 7-8 mm including a 90°turn from white matter into gray matter. Furthermore, expression of semaphorin 3A slightly dorsal and lateral to the turning point increased the number of axons turning into the striatal target. These results show that judicious expression of neuron-specific chemoattractant and chemorepellant molecules using viral vectors can support and target axon growth from neuronal transplants in the adult CNS.

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Section: Discussionmentioning

confidence: 93%

Targeting Axon Growth from Neuronal Transplants along Preformed Guidance Pathways in the Adult CNS

Ziemba¹,

Chaudhry²,

Rabchevsky³

et al. 2008

J. Neurosci.

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“…Activated astrocytes are the main cell type present in the glial scar. Both in vitro and in vivo, activated astrocytes express neurite outgrowth-inhibitory CSPGs (McKeon et al, 1999;Asher et al, 2000;Davies et al, 2004). This makes them an appropriate target for CSPG biosynthesis inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Inhibiting Glycosaminoglycan Chain Polymerization Decreases the Inhibitory Activity of Astrocyte-Derived Chondroitin Sulfate Proteoglycans

Laabs

Wang²,

Katagiri³

et al. 2007

J. Neurosci.

109

101

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Chondroitin sulfate proteoglycans (CSPGs) are upregulated in the CNS after injury and participate in the inhibition of axon regeneration mainly through their glycosaminoglycan (GAG) side chains. In the present study, we have identified a new way to alleviate the inhibition of axonal regeneration by CSPG GAGs. We have successfully decreased the amount of CSPG GAG produced by astrocytes by targeting chondroitin polymerizing factor (ChPF), a key enzyme in the CSPG biosynthetic pathway. Using short interfering RNA (siRNA), we reduced ChPF mRNA levels by 70% in both the Neu7 astrocyte cell line and primary rat astrocytes. This reduction leads to a decrease in ChPF protein levels and a reduced amount of CSPG GAG chains in the conditioned media (CM) of these cells. Secretion of neurocan by primary astrocytes and NG2 core protein by Neu7 cells transfected with ChPF siRNA is not decreased, suggesting that inhibiting GAG chain synthesis does not affect core protein trafficking from these cells. CM from siRNA-treated Neu7 cells is a less repulsive substrate for axons than CM from control cells. In addition, axonal outgrowth from cerebellar granule neurons is increased on or in CM from ChPF siRNA-treated Neu7 cells. These data indicate that targeting the biosynthesis of CSPG GAG is a potentially new therapeutic avenue for decreasing CSPG GAG produced by astrocytes after CNS injury.

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“…It would not be unreasonable to assume that these soluble, large molecules cannot easily diffuse out of damaged and necrotic tissue since diffusion coefficients for most molecules, even sodium, are significantly reduced in postmortem brain relative to living brain (Goodman et al 2005). Also, following TBI, increases in proteoglycan production have been reported (Asher et al 2000;Sherman & Back 2008). The effect could exacerbate oedema in the chronic phase by increasing the FCD in the injured brain (Lai et al 1991;Sun et al 2004;Wang et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Fixed negative charge and the Donnan effect: a description of the driving forces associated with brain tissue swelling and oedema

Elkin

Shaik

Morrison

2010

Phil. Trans. R. Soc. A.

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Cerebral oedema or brain tissue swelling is a significant complication following traumatic brain injury or stroke that can increase the intracranial pressure (ICP) and impair blood flow. Here, we have identified a potential driver of oedema: the negatively charged molecules fixed within cells. This fixed charge density (FCD), once exposed, could increase ICP through the Donnan effect. We have shown that metabolic processes and membrane integrity are required for concealing this FCD as slices of rat cortex swelled immediately (within 30 min) following dissection if treated with 2 deoxyglucose + cyanide (2DG+CN) or Triton X-100. Slices given ample oxygen and glucose, however, did not swell significantly. We also found that dead brain tissue swells and shrinks in response to changes in ionic strength of the bathing medium, which suggests that the Donnan effect is capable of pressurizing and swelling brain tissue. As predicted, a non-ionic osmolyte, 1,2 propanediol, elicited no volume change at 2000 × 10 −3 osmoles l −1 (Osm). Swelling data were well described by triphasic mixture theory with the calculated reference state FCD similar to that measured with a 1,9 dimethylmethylene blue assay. Taken together, these data suggest that intracellular fixed charges may contribute to the driving forces responsible for brain swelling.

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Neurocan Is Upregulated in Injured Brain and in Cytokine-Treated Astrocytes

Cited by 447 publications

References 65 publications

Targeting Axon Growth from Neuronal Transplants along Preformed Guidance Pathways in the Adult CNS

Targeting Axon Growth from Neuronal Transplants along Preformed Guidance Pathways in the Adult CNS

Inhibiting Glycosaminoglycan Chain Polymerization Decreases the Inhibitory Activity of Astrocyte-Derived Chondroitin Sulfate Proteoglycans

Fixed negative charge and the Donnan effect: a description of the driving forces associated with brain tissue swelling and oedema

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