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)

A number of recent studies have established that the bacterial enzyme chondroitinase ABC promotes functional recovery in the injured CNS. The issue of how it works is rarely addressed, however. The effects of the enzyme are presumed to be due to the degradation of inhibitory chondroitin sulphate GAG chains. Here we review what is known about the composition, structure and distribution of the extracellular matrix in the CNS, and how it changes in response to injury. We summarize the data pertaining to the ability of chondroitinase to promote functional recovery, both in the context of axon regeneration and the reactivation of plasticity. We also present preliminary data on the persistence of the effects of the enzyme in vivo, and its hyaluronan-degrading activity in CNS homogenates in vitro. We then consider precisely how the enzyme might influence functional recovery in the CNS. The ability of chondroitinase to degrade hyaluronan is likely to result in greater matrix disruption than the degradation of chondroitin sulphate alone.
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PMID:How does chondroitinase promote functional recovery in the damaged CNS? 1757 6

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

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

Exercise provides a number of important benefits after spinal cord injury in clinical studies and animal models. However, the amount of functional improvement in overground locomotion obtained with exercise alone has been limited thus far, for reasons that are still poorly understood. One hypothesis is that the complex network of endogenous extracellular matrix components, including chondroitin sulfate proteoglycans (CSPGs), can inhibit exercise-induced remodeling and limit plasticity of spared circuitry in the adult central nervous system. Recent animal studies have shown that chondroitinase ABC (ChABC) can enhance plasticity in the adult nervous system by cleaving glycosaminoglycan sidechains from CSPGs. In this article we review the current literature on plasticity observed with locomotor training and following degradation of CSPGs with ChABC and then present a rationale for the use of exercise combined with ChABC to promote functional recovery after spinal cord injury. We also present results of a preliminary study that tested the simplest approach for combining these treatments; use of a single intraparenchymal injection of ChABC administered to the lumbar enlargement of mice with voluntary wheel running exercise after a mid-thoracic spinal contusion injury. The results are negative, yet serve to highlight limitations in our understanding of the most effective protocols for combining these approaches. Further work is directed to identify the timing, type, and quantity of exercise and pharmacological interventions that can be used to maximize functional improvements by strengthening appropriate synaptic connections.
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PMID:Injured mice at the gym: review, results and considerations for combining chondroitinase and locomotor exercise to enhance recovery after spinal cord injury. 2055 54

Chondroitin sulphate proteoglycans (CSPGs) are potent inhibitors of growth in the adult CNS. Use of the enzyme chondroitinase ABC (ChABC) as a strategy to reduce CSPG inhibition in experimental models of spinal cord injury has led to observations of a remarkable capacity for repair. Here we review the evidence that treatment with ChABC, either as an individual therapy or in combination with other strategies, can have multiple beneficial effects on promoting repair following spinal cord injury. These include promoting regeneration of injured axons, plasticity of uninjured pathways and neuroprotection of injured projection neurons. More importantly, ChABC therapy has been demonstrated to promote significant recovery of function to spinal injured animals. Thus, there is robust pre-clinical evidence demonstrating beneficial effects of ChABC treatment following spinal cord injury. Furthermore, these effects have been replicated in a number of different injury models, with independent confirmation by different laboratories, providing an important validation of ChABC as a promising therapeutic strategy. We discuss putative mechanisms underlying ChABC-mediated repair as well as potential issues and considerations in translating ChABC treatment into a clinical therapy for spinal cord injury.
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PMID:Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury. 2062 Feb 1

Growth-inhibitory chondroitin sulfate proteoglycans (CSPGs) contribute a lot to failure of axon regeneration. Chondroitinase ABC (ChABC) digests glycosaminoglycan chains attached in CSPGs and can thereby promote axonal regeneration beyond a lesion site. However, CSPGs expression are up-regulated for almost 7 weeks after spinal cord injury (SCI) in vivo, so single dose of exogenous ChABC is insufficient for long distance of axon sprout and functional recovery. It is considered an ideal strategy to transfect neurons and/or glia at the injury site with a vector containing the gene encoding chondroitinase, so they can secrete ChABC themselves. Mammalian cells in the current studies, however, can not secret ChABC efficiently. It is well established that glycosylation is a common obstacle for eukaryotic cells to secret bacterial protein. ChABC is a protein heavily glycosylated structurally, and it was reported that inhibiting the glycosylation of xylosyltransferase-1 with a DNA enzyme could reduce GAG chains in the lesion of spinal cord. So presence of glycosylation sites in the bacterial sequence is supposed the barrier that preventing ChABC secretion from mammalian cells. We intend to mutate the key N-glycosylation sites of the bacterial ChABC sequence and transduce it into BMSCs by lentivirus vector. The modified BMSCs are expected to promote axon regeneration through multiple mechanisms, providing sustained ChABC and neurotrophic factors, as well as filling in the cavities formed post-trauma. The transduced BMSCs with gene mutated in key glycosylation sites in the present hypothesis provide a promising strategy to promote axon regeneration.
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PMID:Secretion of bacterial chondroitinase ABC from bone marrow stromal cells by glycosylation site mutation: a promising approach for axon regeneration. 2188 1

Application of chondroitinase ABC (ChABC) to injured peripheral nerves improves axon regeneration, but it is not known whether functional recovery is also improved. Recordings of EMG activity [soleus (Sol) M response and H reflexes] evoked by nerve stimulation and of Sol and tibialis anterior (TA) EMG activity and hindlimb and foot kinematics during slope walking were made to determine whether ChABC treatment of the sciatic nerve at the time of transection improves functional recovery. Recovery of evoked EMG responses began as multiple small responses with a wide range of latencies that eventually coalesced into one or two more distinctive and consistent responses (the putative M response and the putative H reflex) in both groups. Both the initial evoked responses and the time course of their maturation returned sooner in the ChABC group than in the untreated (UT) group. The reinnervated Sol and TA were coactivated during treadmill locomotion during downslope, level, and upslope walking throughout the study period in both UT and ChABC-treated rats. By 10 wk after nerve transection and repair, locomotor activity in Sol, but not TA, had returned to its pretransection pattern. There was an increased reliance on central control of Sol activation across slopes for both groups as interpreted from elevated prestance Sol EMG activity that was no longer modulated with slope. Limb length and orientation during locomotion were similar to those observed prior to nerve injury during upslope walking only in the ChABC-treated rats. Thus treatment of cut nerves with ChABC leads to improvements in functional recovery.
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PMID:Chondroitinase ABC reduces time to muscle reinnervation and improves functional recovery after sciatic nerve transection in rats. 2204 33

This study aimed to evaluate whether combination therapy of bone marrow stromal cells (BMSCs) transplantation and chondroitinase ABC (ChABC) treatment further enhances axonal regeneration and functional recovery after acellular nerve allograft repair of the sciatic nerve gap in rats. Eight Sprague-Dawley rats were used as nerve donors, and 32 Wistar rats were randomly divided into four groups: Group I: acellular rat sciatic nerve (ARSN) group; Group II: ChABC treatment; Group III: BMSCs transplantation; and Group IV: ChABC treatment and BMSCs transplantation. The results showed that compared with ARSN control group, BMSC transplantation promoted axonal regeneration, the secretion of neural trophic factors NGF, BDNF and axon angiogenesis in nerve graft. ChABC treatment degraded chondroitin sulfate proteoglycans in ARSN in vitro and in vivo and improved BMSCs survival in ARSN. The combination therapy caused much better beneficial effects evidenced by increasing sciatic function index, nerve conduction velocity, restoration rate of tibialis anterior wet muscle weight, and myelinated nerve number, but did not further boost the therapeutic effects on neurotrophic factor production, axon angiogenesis, and sensory functional recovery by BMSC transplantation. Taken together, for the first time, we demonstrate the synergistic effects of BMSC transplantation and BMSCs treatment on peripheral nerve regeneration, and our findings may help establish novel strategies for cell transplantation therapy for peripheral nerve injury.
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PMID:Synergistic effects of bone mesenchymal stem cells and chondroitinase ABC on nerve regeneration after acellular nerve allograft in rats. 2209 68

Elevating spinal levels of neurotrophin NT-3 (NT3) while increasing expression of the NR2D subunit of the NMDA receptor using a HSV viral construct promotes formation of novel multisynaptic projections from lateral white matter (LWM) axons to motoneurons in neonates. However, this treatment is ineffective after postnatal day 10. Because chondroitinase ABC (ChABC) treatment restores plasticity in the adult CNS, we have added ChABC to this treatment and applied the combination to adult rats receiving a left lateral hemisection (Hx) at T8. All hemisected animals initially dragged the ipsilateral hindpaw and displayed abnormal gait. Rats treated with ChABC or NT3/HSV-NR2D recovered partial hindlimb locomotor function, but animals receiving combined therapy displayed the most improved body stability and interlimb coordination [Basso-Beattie-Bresnahan (BBB) locomotor scale and gait analysis]. Electrical stimulation of the left LWM at T6 did not evoke any synaptic response in ipsilateral L5 motoneurons of control hemisected animals, indicating interruption of the white matter. Only animals with the full combination treatment recovered consistent multisynaptic responses in these motoneurons indicating formation of a detour pathway around the Hx. These physiological findings were supported by the observation of increased branching of both cut and intact LWM axons into the gray matter near the injury. ChABC-treated animals displayed more sprouting than control animals and those receiving NT3/HSV-NR2D; animals receiving the combination of all three treatments showed the most sprouting. Our results indicate that therapies aimed at increasing plasticity, promoting axon growth and modulating synaptic function have synergistic effects and promote better functional recovery than if applied individually.
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PMID:Chondroitinase ABC combined with neurotrophin NT-3 secretion and NR2D expression promotes axonal plasticity and functional recovery in rats with lateral hemisection of the spinal cord. 2215 95


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