Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.6.4 (chondroitinase)
2,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Damage to the adult CNS often causes devastating and permanent deficits because of the limited capacity of the brain for anatomical reorganization. The finding that collateral sprouting of uninjured fiber tracts mediates recovery of function prompts the search for experimental strategies that stimulate axonal plasticity after CNS trauma. Here we characterize treatments that promote the sprouting of undamaged retinal afferents into the denervated superior colliculus (SC) after a partial retinal lesion in the adult rat. Delivery of brain-derived neurotrophic factor (BDNF) was performed to enhance the intrinsic potential of retinal ganglion cells to reelongate their axons. Reduction of the neurite growth-inhibitory properties of the adult SC was accomplished via treatment with chondroitinase ABC (C-ABC), which degrades chondroitin sulfate proteoglycans. Retinal axons were labeled via intraocular injections of fluorescently tagged cholera toxin B subunit, and fiber sprouting within the denervated SC was measured by quantitative laser-scanning confocal microscopy 1 week after the retinal lesion. We found that both the administration of BDNF and the injection of C-ABC induce significant sprouting of retinal afferents into the collicular scotoma. Remarkably, the combined treatment with BDNF and C-ABC showed synergistic effects on axon growth. Colocalization analysis with anti-synapsin antibodies demonstrated synapse formation by the sprouting axons. These results suggest that the combined treatment with BDNF and C-ABC can be relevant in therapies for the repair of the damaged adult CNS.
...
PMID:Synergistic effects of brain-derived neurotrophic factor and chondroitinase ABC on retinal fiber sprouting after denervation of the superior colliculus in adult rats. 1290 64

Grafting of Schwann cell-seeded channels into hemisected adult rat thoracic spinal cords has been tested as a strategy to bridge the injured cord. Despite success in guiding axonal growth into the graft, regeneration across the distal graft-host interface into the host spinal cord was limited. We hypothesized that chondroitin sulfate (CS) glycoforms deposited at the gliotic front of the interface constitute a molecular barrier to axonal growth into the host cord. Because CS glycoforms deposited by purified astrocytes in vitro were removable by digestion with chondroitinase ABC, we attempted to achieve likewise by infusion of the enzyme to the host side of the interface. By 1 month post-treatment, significant numbers of regenerating axons crossed an interface that was subdued in macrophage/microglia reaction and decreased in CS-immunopositivity. The axons extended as far into the caudal cord as 5 mm, in contrast to nil in vehicle-infused controls. Fascicular organizations of axon-Schwann cell units within the regenerated tissue cable were better-preserved in enzyme-treated cords than in vehicle-infused controls. We conclude that CS glycoforms deposited during gliosis at the distal graft-host interface could be cleared by the in vivo action of chondroitinase ABC to improve prospects of axonal regeneration into the host spinal cord.
...
PMID:Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury. 1463 Jul 2

It is well established that axonal regeneration in the adult CNS is largely unsuccessful. Numerous axon-inhibitory molecules are now known to be present in the injured CNS, and various strategies for overcoming these obstacles and enhancing CNS regeneration have been experimentally developed. Recently, the use of chondroitinase-ABC to treat models of CNS injury in vivo has proven to be highly beneficial towards regenerating axons, by degrading the axon-inhibitory chondroitin sulphate glycosaminoglycan chains found on many proteoglycans in the astroglial scar. This enzyme has now been shown to restore synaptic plasticity in the visual cortex of adult rats by disrupting perineuronal nets, which contain high levels of chondroitin sulphate proteoglycans (CS-PGs) and are expressed postnatally around groups of certain neurons in the normal CNS. The findings suggest exciting prospects for enhancing growth and plasticity in the adult CNS; however, some protective roles of CS-PGs in the CNS have also been demonstrated. Clearly many questions concerning the mechanisms regulating expression of extracellular matrix molecules in CNS pathology remain to be answered.
...
PMID:Chondroitin sulphate proteoglycans: preventing plasticity or protecting the CNS? 1469 Apr 76

During the initial stages of development, the notochord provides repulsive signals for dorsal root ganglion (DRG) axons via semaphorin 3A/neuropilin-1, axonin-1/SC2, and other unknown repulsive molecules. The notochord is known to produce aggrecan, one of the chondroitin sulfate proteoglycans (CSPGs). We report here that adding aggrecan to the culture medium cannot only induce DRG growth cone collapse, but also inhibit DRG axonal growth. Using cocultures composed of tissues derived from chick embryos or neuropilin-1-deficient mice treated with chondroitinase ABC, we show the direct evidence that CSPGs are involved in notochord-derived repulsion for DRG axons. At later developmental stages, CSPGs are involved in perinotochordal sheath-derived axon repulsion, but not in notochord core-derived repulsion. We further demonstrate that TAG-1/axonin-1/SC2 is not involved in mediating repulsive activities by CSPGs, but is required for notochord core-derived axon repulsion. Thus, notochord-derived multiple axon repulsions act in a spatiotemporal-specific manner to shape the initial trajectories of DRG axons.
...
PMID:Developmental regulation of notochord-derived repulsion for dorsal root ganglion axons. 1501 39

After spinal cord injury, enzymatic digestion of chondroitin sulfate proteoglycans promotes axonal regeneration of central nervous system neurons across the lesion scar. We examined whether chondroitinase ABC (ChABC) promotes the axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord. The effect of a GSK-3beta inhibitor, lithium chloride (LiCl), on the regeneration of axotomized RST neurons was also assessed. Adult rats received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after different treatments, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2, and locomotor recovery was studied by a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury, and intraperitoneal injection of LiCl alone did not promote the regeneration of RST axons. Administration of ChABC at the lesion site enhanced the regeneration of RST axons by 20%. Combined treatment of LiCl together with ChABC significantly increased the regeneration of RST axons to 42%. Animals receiving combined treatment used both forelimbs together more often than animals that received sham or single treatment. Immunoblotting and immunohistochemical analysis revealed that LiCl induced the expression of inactive GSK-3beta as well as the upregulation of Bcl-2 in injured RST neurons. These results indicate that in vivo, LiCl inhibits GSK-3beta and reinforces the regeneration-promoting function of ChABC through a Bcl-2-dependent mechanism. Combined use of LiCl together with ChABC could be a novel treatment for spinal cord injury.
...
PMID:Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. 1530 5

Proteoglycan is a family of glycoproteins which carry covalently-linked glycosaminoglycan chains, such as chondroitin sulfate and heparan sulfate. Proteoglycans are believed to play important roles in morphogenesis and maintenance of various tissues including the central nervous system (CNS) through interactions with cell adhesion molecules and growth factors. In the CNS, a significant amount of evidence has been accumulated to show that proteoglycans function as modulators in various cellular events not only in the development, but also in the pathogenesis of neuronal diseases and lesions. When the CNS is injured, several chondroitin sulfate proteoglycans (CSPG) are up-regulated in glial scars formed around the lesion site. The glial scar also contains some molecules inhibitory to axonal growth, such as myelin-associated glycoprotein, Nogo, and Semaphorin. In vitro studies revealed that CSPG largely exert a repulsive effect on axonal regeneration, and a signal from CSPG modulates the actin cytoskeleton of outgrowing neurites through the Rho/ROCK pathway. These findings suggest that CSPG are responsible for unsuccessful axonal regeneration in glial scars. Various attempts to overcome the inhibitory effect of CSPG have been pursued in vivo. Digestion of chondroitin sulfate chains by chondroitinase ABC, suppression of CSPG core protein synthesis by decorin, suppression of glycosaminoglycan chain synthesis by a DNA enzyme, and inhibition of the Rho/ROCK pathway with specific inhibitors were all successful for increasing axonal regeneration. For a clinical application, the most effective combination of these treatments needs to be examined in the future.
...
PMID:Proteoglycans and injury of the central nervous system. 1556 8

Numerous obstacles to successful regeneration of injured axons in the adult mammalian spinal cord exist. Consequently, a treatment strategy inducing axonal regeneration and significant functional recovery after spinal cord injury has to overcome these obstacles. The current study attempted to address multiple impediments to regeneration by using a combinatory strategy after complete spinal cord transection in adult rats: (1) to reduce inhibitory cues in the glial scar (chondroitinase ABC), (2) to provide a growth-supportive substrate for axonal regeneration [Schwann cells (SCs)], and (3) to enable regenerated axons to exit the bridge to re-enter the spinal cord (olfactory ensheathing glia). The combination of SC bridge, olfactory ensheathing glia, and chondroitinase ABC provided significant benefit compared with grafts only or the untreated group. Significant improvements were observed in the Basso, Beattie, and Bresnahan score and in forelimb/hindlimb coupling. This recovery was accompanied by increased numbers of both myelinated axons in the SC bridge and serotonergic fibers that grew through the bridge and into the caudal spinal cord. Although prominent descending tracts such as the corticospinal and reticulospinal tracts did not successfully regenerate through the bridge, it appeared that other populations of regenerated fibers were the driving force for the observed recovery; there was a significant correlation between numbers of myelinated fibers in the bridge and improved coupling of forelimb and hindlimb as well as open-field locomotion. Our study tests how proven experimental treatments interact in a well-established animal model, thus providing needed direction for the development of future combinatory treatment regimens.
...
PMID:Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. 1568 53

Chondroitin sulfate proteoglycans are major constituents of the extracellular matrix and form perineuronal nets. Information regarding the growth-inhibitory activity of these molecules after injury is rapidly expanding. However, less is known about their physiological role in the adult undamaged CNS. Here, we investigated the function of chondroitin sulfate proteoglycans in maintaining the proper structure of Purkinje axons in the cerebellum of adult rats. To this end, we examined the morphology and distribution of intracortical Purkinje neurites after intraparenchymal injection of chondroitinase ABC. Staining with the lectin Wisteria floribunda agglutinin or 2B6 antibodies showed that this treatment efficiently removed chondroitin sulfate proteoglycans from wide areas of the cerebellar cortex. In the same sites, there was a profuse outgrowth of terminal branches from the Purkinje infraganglionic plexus, which invaded the deeper regions of the granular layer. In contrast, myelinated axon segments were not affected and maintained their normal relationship with oligodendroglial sheaths. Purkinje axon sprouting was first evident at 4 d and increased further at 7 d after enzyme application. Within 42 d, the expression pattern of chondroitin sulfate proteoglycans gradually recovered, whereas axonal modifications progressively regressed. Our results show that, in the absence of injury or novel external stimuli, degradation of chondroitin sulfate proteoglycans is sufficient to induce Purkinje axon sprouting but not the formation of long-lasting synaptic contacts. Together with other growth-inhibitory molecules, such as myelin-associated proteins, chondroitin sulfate proteoglycans restrict structural plasticity of intact Purkinje axons to maintain normal wiring patterns in the adult cerebellar cortex.
...
PMID:Degradation of chondroitin sulfate proteoglycans induces sprouting of intact purkinje axons in the cerebellum of the adult rat. 1607 97

Chondroitin sulfate proteoglycan (CSPG), a matrix protein that occurs naturally in the central nervous system (CNS), is considered to be a major inhibitor of axonal regeneration and is known to participate in activation of the inflammatory response. The degradation of CSPG by a specific enzyme, chondroitinase ABC, promotes repair. We postulated that a disaccharidic degradation product of this glycoprotein (CSPG-DS), generated following such degradation, participates in the modulation of the inflammatory responses and can, therefore, promote recovery in immune-induced neuropathologies of the CNS, such as experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveitis (EAU). In these pathologies, the dramatic increase in T cells infiltrating the CNS is far in excess of the numbers needed for regular maintenance. Here, we show that CSPG-DS markedly alleviated the clinical symptoms of EAE and protected against the neuronal loss in EAU. The last effect was associated with a reduction in the numbers of infiltrating T cells and marked microglia activation. This is further supported by our in vitro results indicating that CSPG-DS attenuated T cell motility and decreased secretion of the cytokines interferon-gamma and tumor necrosis factor-alpha. Mechanistically, these effects are associated with an increase in SOCS-3 levels and a decrease in NF-kappaB. Our results point to a potential therapeutic modality, in which a compound derived from an endogenous CNS-resident molecule, known for its destructive role in CNS recovery, might be helpful in overcoming inflammation-induced neurodegenerative conditions.
...
PMID:A sulfated disaccharide derived from chondroitin sulfate proteoglycan protects against inflammation-associated neurodegeneration. 1639 93

Damaged axons do not regenerate after axotomy in the adult mammalian central nervous system (CNS). This may be due to local inhibitory factors at the site of injury, such as overexpression of chondroitin sulfate (CS) proteoglycans (CSPG), and the presence of myelin-associated inhibitors (MAI). To overcome CSPG- or myelin-induced inhibition, strategies based on extrinsic and intrinsic treatments have been developed. For example, NEP1-40 is a synthetic peptide that promotes axonal regeneration by blocking Nogo-66/NgR interaction and chondroitinase ABC (ChABC), which degrades CS, thereby also promoting axon regrowth. Here, we examined whether the combination of these complementary strategies facilitates regeneration of the lesioned entorhino-hippocampal pathway (EHP) in slice cultures. In this model, overexpressed CSPG and MAI impaired axon regrowth, which mimics regeneration failure in vivo. Both CS cleavage with ChABC and NEP1-40 strongly facilitated the regrowth of entorhinal axons after axotomy, permitting the re-establishment of synaptic contacts with target cells. However, the combined treatment did not improve the regeneration induced by ChABC alone, and the delayed treatment of ChABC, but not NEP1-40, had a less pronounced effect on axonal regrowth compared with acute treatment. These results provide insight into the development of new assays and strategies to enhance axon regeneration in injured cortical connections.
...
PMID:Regeneration of lesioned entorhino-hippocampal axons in vitro by combined degradation of inhibitory proteoglycans and blockade of Nogo-66/NgR signaling. 1640 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---