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

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

Paralysis resulting from spinal cord injury is devastating and persistent. One major reason for the inability of the body to heal this type of injury ensues from the local increase of glial cells leading to the formation of a glial scar, and the upregulation of chondroitin sulfate proteoglycans (CSPGs) at the site of injury through which axons are unable to regenerate. Experimental approaches to overcome this problem have accordingly focused on reducing the inhibitory properties of CSPGs, for example by using chondroitinase to remove the sugar chains and reduce the CSPGs to their core protein constituents, although this step alone does not provide dramatic benefits as a monotherapy. Using in vitro and in vivo approaches, we describe here a potentially synergistic therapeutic opportunity based on tissue plasminogen activator (tPA), an extracellular protease that converts plasminogen (plg) into the active protease plasmin. We show that tPA and plg both bind to the CSPG protein NG2, which functions as a scaffold to accelerate the tPA-driven conversion of plg to plasmin. The binding occurs via the tPA and plg kringle domains to domain 2 of the NG2 CSPG core protein, and is enhanced in some settings after chondroitinase-mediated removal of the NG2 proteoglycan side chains. Once generated, plasmin then degrades NG2, both in an in vitro setting using recombinant protein, and in vivo models of spinal cord injury. Our finding that the tPA and plg binding is in some instances more efficient after exposure of the NG2 proteoglycan to chondroitinase treatment suggests that a combined therapeutic approach employing both chondroitinase and the tPA/plasmin proteolytic system could be of significant benefit in promoting axonal regeneration through glial scars after spinal cord injury.
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PMID:tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2. 1800 Aug 64

We evaluated the effects of chondroitinase ABC on axonal regeneration across peripheral nerve gaps. We compared axonal regeneration after 15-mm tibial nerve resection and repair with a silicone tube filled with type I collagen gel (negative control group), with a silicone tube filled with type I collagen gel containing chondroitinase ABC at three different concentrations (2.5 units/mL, 5 units/mL, 10 units/mL) (chondroitinase ABC groups), and with an autologous nerve segment (nerve autograft group). Electrophysiological and histological assessments were carried out 12 weeks after surgery. In the electrophysiological study, compound muscle action potentials (CMAPs) and nerve conduction velocities (NCVs) were recorded in all groups except the negative control group. Although both CMAPs and NCVs were highest in the nerve autograft group, there were no significant differences among the three chondroitinase ABC groups in either parameter. Histological findings were consistent with electrophysiological results. Based on these findings, we conclude that topical injection of chondroitinase ABC can significantly increase the critical length of nerve gap repair by tubulization or artificial nerve placement.
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PMID:Chondrotinase ABC enhances axonal regeneration across nerve gaps. 1807 54

Spinal cord injuries devastate the lives of those affected. Normally, acute injury leads to chronic injury in the spinal cord, although this has a variable impact on normal sensory and motor functions. Currently the only drug used to treat acute spinal cord injury is methyl-prednisolone, administered in order to prevent secondary inflammatory neural damage. Thus, it is time that alternative and complementary pharmacological, cell and gene therapies be developed. In order to achieve this, several approaches to stimulate spinal cord repair must be considered. Indeed, the main lines of research that have been established in different animal models of spinal cord regeneration are now beginning to produce encouraging results. Several patents have been derived from these studies and hopefully, they will lead to the development of new treatments for human spinal cord injuries. Here is presented a review of the main patents that have been generated by this research, and that can be classified as: - Patents involving the use of different factors that promote axonal regeneration. - Patents aimed at overcoming the activity of glial scar inhibitory molecules that hinder axonal regeneration. These approaches can be further subdivided into those that block Nogo and other myelin components, and those that involve the use of chondroitinase against glial scar chondroitin sulphate proteoglycans. - Patents concerning glial cell therapy, in which glial cells are used to mediate axonal repair in the spinal cord (Schwann cells, olfactory ensheathing cells or astrocytes).
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PMID:The quest to repair the damaged spinal cord. 1822 Nov 91

Chondroitin sulfate proteoglycans (CSPG) within the glial scar formed after central nervous system (CNS) injury are thought to play a crucial role in regenerative failure. We previously showed that delivery of the CSPG-digesting enzyme chondroitinase ABC (ChABC) via an osmotic minipump allowed axonal regeneration and functional recovery in a peripheral nerve graft (PNG)-bridging model. In this study, we sought to overcome the technical limitations associated with minipumps by microinjecting ChABC directly into the distal lesion site in the PN bridging model. Microinjection of ChABC immediately rostral and caudal to an injury site resulted in extensive CSPG digestion. We also demonstrate that this delivery technique is relatively atraumatic and does not result in a noticeable inflammatory response. Importantly, microinjections of ChABC into the lesion site permitted more regenerating axons to exit a PNG and reenter spinal cord tissue than saline injections. These results are similar to our previous findings when ChABC was delivered via a minipump and suggest that microinjecting ChABC is an effective method of delivering the potentially therapeutic enzyme directly to an injury site.
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PMID:Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve graft bridge. 1835 13

Chondroitin sulfate proteoglycans (CSPGs) inhibit axonal growth, and treatment with chondroitinase ABC promotes axonal regeneration in some models of central nervous system (CNS) injury. The aims of this study were (1) to compare the spatiotemporal appearance of CSPG expression between spinal cord contusion and hemisection models, and (2) to evaluate chondroitinase treatment effects on axonal regrowth in the two injury models. After hemisection, CSPG-immunoreactivity (IR) in the injury site rose to peak levels at 18 days but then decreased dramatically by 49 days; in contrast, CSPG-IR remained high for at least 49 days after contusion. After hemisection, many anterogradely labeled corticospinal tract (CST) axons remained close to CSPG-rich lesion sites, but after contusion, most CST axons retracted by approximately 1 mm rostral from the rostral-most CSPG-rich cyst. Intraspinal injection of chondroitinase at 0, 1, 2, and 4 weeks following injury dramatically reduced CSPG-IR in both injury models within 4 days, and CSPG-IR remained low for at least 3 weeks. After the chondroitinase treatment, many axons grew around the lesion site in hemisected spinal cords but not in contused spinal cords. We propose that improved axonal growth in hemisected spinal cords is due to decreased inhibition resulting from degradation of CSPGs located adjacent to severed CST axons. However, in spinal cord contusions, retracted CST axons fail to grow across gliotic regions that surround CSPG-rich injury sites despite efficient degradation with chondroitinase, suggesting that other inhibitors of axonal growth persist in the gliotic regions.
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PMID:Single, high-dose intraspinal injection of chondroitinase reduces glycosaminoglycans in injured spinal cord and promotes corticospinal axonal regrowth after hemisection but not contusion. 1837 83

Due to the varied and numerous changes in spinal cord tissue following injury, successful treatment for repair may involve strategies combining neuroprotection (pharmacological prevention of some of the damaging intracellular cascades that lead to secondary tissue loss), axonal regeneration promotion (cell transplantation, genetic engineering to increase growth factors, neutralization of inhibitory factors, reduction in scar formation), and rehabilitation. Our goal has been to find effective combination strategies to improve outcome after injury to the adult rat thoracic spinal cord. Combination interventions tested have been implantation of Schwann cells (SCs) plus neuroprotective agents and growth factors administered in various ways, olfactory ensheathing cell (OEC) implantation, chondroitinase addition, or elevation of cyclic AMP. The most efficacious strategy in our hands for the acute complete transection/SC bridge model, including improvement in locomotion [Basso, Beattie, Bresnahan Scale (BBB)], is the combination of SCs, OECs, and chondroitinase administration (BBB 2.1 vs 6.6, 3 times more myelinated axons in the SC bridge, increased serotonergic axons in the bridge and beyond, and significant correlation between the number of bridge myelinated axons and functional improvement). We found the most successful combination strategy for a subacute spinal cord contusion injury (12.5-mm, 10-g weight, MASCIS impactor) to be SCs and elevation of cyclic AMP (BBB 10.4 vs 15, significant increases in white matter sparing, in myelinated axons in the implant, and in responding reticular formation and red and raphe nuclei, and a significant correlation between the number of serotonergic fibers and improvement in locomotion). Thus, in two injury paradigms, these combination strategies as well as others studied in our laboratory have been found to be more effective than SCs alone and suggest ways in which clinical application may be developed.
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PMID:Novel combination strategies to repair the injured mammalian spinal cord. 1879 75

Chondroitin sulfate proteoglycans (CSPGs) consist of chondroitin sulfate (CS) glycosaminoglycans (GAGs) and core protein and regulate the migration, axonal outgrowth, and synaptogenesis in mammalian brains. In the present study, we investigated the localization of CSPGs, the effects of sensory deprivation on the density of perineuronal nets (PNNs), and the effects of chondroitinase ABC (Chase) on the formation of barrel structures in the posterior medial barrel subfield (PMBSF). In developing mouse and rat brains, the immunoreactivity of chondroitin-6-sulfate containing proteoglycan (CS-6-PG), phosphacan, and neurocan was stronger at barrel septa as compared with barrel hollows and surrounding cortex, while the labeling of Wisteria floribunda agglutinin (WFA) was observed at barrel hollows. In adult brains, CS-6-PG-immunoreactive and WFA-labeled PNNs were observed mainly at barrel hollows of mouse, but they were seen chiefly at barrel septa of rats. Sensory deprivation of facial vibrissae reduced the number of WFA-labeled PNNs at barrel hollows but not at barrel septa. Intracerebral injection of Chase did not affect the formation of barrel structures in the PMBSF. These data indicate species-dependent heterogeneity of CSPG expression and activity-dependent formation of PNNs in the PMBSF, but CS GAGs have no crucial function in constructing the barrel structures during early postnatal development.
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PMID:Expression of chondroitin sulfate proteoglycans in barrel field of mouse and rat somatosensory cortex. 1905 58

Traumatic brain injury is often associated with acute spinal cord injury (ASCI). Insulin and chondroitinase ABC (ChABC) are both therapeutically effective, but the combined therapeutic effect of insulin and ChABC is still not clear. A combination of insulin and ChABC were used to treat a rat model of ASCI. This combination therapy prevented neuronal cell death by improving motor function, increasing cell growth and inhibiting cell apoptosis in ASCI rats. Expression of growth-associated protein 43, a marker of axonal re-growth, increased after combined treatment with insulin and ChABC. These results may provide a basis for a future method of treating ASCI.
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PMID:Insulin with chondroitinase ABC treats the rat model of acute spinal cord injury. 1976 92

Traumatic injury to the spinal cord (SCI) causes death of neurons, disruption of motor and sensory nerve fiber (axon) pathways and disruption of communication with the brain. One of the goals of our research is to promote axon regeneration to restore connectivity across the lesion site. To accomplish this we developed a peripheral nerve (PN) grafting technique where segments of sciatic nerve are either placed directly between the damaged ends of the spinal cord or are used to form a bridge across the lesion. There are several advantages to this approach compared to transplantation of other neural tissues; regenerating axons can be directed towards a specific target area, the number and source of regenerating axons is easily determined by tracing techniques, the graft can be used for electrophysiological experiments to measure functional recovery associated with axons in the graft, and it is possible to use an autologous nerve to reduce the possibility of graft rejection. In our lab we have performed both autologous (donor and recipient are the same animal) and heterologous (donor and recipient are different animals) grafts with comparable results. This approach has been used successfully in both acute and chronic injury situations. Regenerated axons that reach the distal end of the PN graft often fail to extend back into the spinal cord, so we use microinjections of chondroitinase to degrade inhibitory molecules associated with the scar tissue surrounding the area of SCI. At the same time we have found that providing exogenous growth and trophic molecules encourages longer distance axonal regrowth into the spinal cord. Several months after transplantation we perform a variety of anatomical, behavioral and electrophysiological tests to evaluate the recovery of function in our spinal cord injured animals. This experimental approach has been used successfully in several spinal cord injury models, at different levels of injury and in different species (mouse, rat and cat). Importantly, the peripheral nerve grafting approach is effective in promoting regeneration by acute and chronically injured neurons.
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PMID:Combining peripheral nerve grafting and matrix modulation to repair the injured rat spinal cord. 1993 38

Because there currently is no treatment for spinal cord injury, most patients are living with long-standing injuries. Therefore, strategies aimed at promoting restoration of function to the chronically injured spinal cord have high therapeutic value. For successful regeneration, long-injured axons must overcome their poor intrinsic growth potential as well as the inhibitory environment of the glial scar established around the lesion site. Acutely injured axons that regenerate into growth-permissive peripheral nerve grafts (PNGs) reenter host tissue to mediate functional recovery if the distal graft-host interface is treated with chondroitinase ABC (ChABC) to cleave inhibitory chondroitin sulfate proteoglycans in the scar matrix. To determine whether a similar strategy is effective for a chronic injury, we combined grafting of a peripheral nerve into a highly relevant, chronic, cervical contusion site with ChABC treatment of the glial scar and glial cell line-derived neurotrophic factor (GDNF) stimulation of long-injured axons. We tested this combination in two grafting paradigms: (1) a peripheral nerve that was grafted to span a chronic injury site or (2) a PNG that bridged a chronic contusion site with a second, more distal injury site. Unlike GDNF-PBS treatment, GDNF-ChABC treatment facilitated axons to exit the PNG into host tissue and promoted some functional recovery. Electrical stimulation of axons in the peripheral nerve bridge induced c-Fos expression in host neurons, indicative of synaptic contact by regenerating fibers. Thus, our data demonstrate, for the first time, that administering ChABC to a distal graft interface allows for functional axonal regeneration by chronically injured neurons.
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PMID:Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord. 1994 Jan 84


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