chondroitin-sulfates and Spinal-Cord-Injuries
chondroitin-sulfates has been researched along with Spinal-Cord-Injuries* in 30 studies
Reviews
1 review(s) available for chondroitin-sulfates and Spinal-Cord-Injuries
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Chondroitin sulfate: a key molecule in the brain matrix.
Chondroitin sulfate is a glycosaminoglycan composed of N-acetylgalactosamine and glucuronic acid. It attaches to a core protein to form chondroitin sulfate proteoglycan (CSPG). Being a major component of the brain extracellular matrix, CSPGs are involved in neural development, axon pathfinding and guidance, plasticity and also regeneration after injury in the nervous system. In this review, we shall discuss the structure, the biosynthetic pathway, its functions in the nervous system and how we can improve regeneration in the nervous system by modulating its structure and binding properties. Topics: Animals; Brain; Brain Injuries; Chondroitin Sulfates; Gene Expression Regulation; Humans; Neuronal Plasticity; Spinal Cord Injuries | 2012 |
Other Studies
29 other study(ies) available for chondroitin-sulfates and Spinal-Cord-Injuries
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Intravesical hyaluronic acid with chondroitin sulphate to prevent urinary tract infection after spinal cord injury.
Prevention of urinary tract infection (UTI) after spinal cord injury is an important goal. Intravesical hyaluronic acid with chondroitin sulphate (HA+CS) has been effective in preventing UTI in other settings. We aimed to demonstrate safety and feasibility of a standard treatment course of 7 intravesical HA+CS instillations over 12 weeks, in patients with acute (Arm A) and chronic (Arm B) spinal cord injury (SCI).. Follow-up of adverse events, quality of life bladder management difficulty (BMD) and bladder complication (BC). Of 33 and 14 individuals screened, 2 and 8 participants were recruited to the study for Arm A and Arm B respectively. Of the 10 participants, 8 completed all 7 instillations. HA+CS commonly caused cloudy urine with urinary sediment which was mild and short-lived. In Arm B, a mean reduction in BMD and BC T-scores was observed from baseline (57.3 and 54.4 respectively), of 6.8 and 4.3 at 12 weeks and 1.6 and 2.8 at 24 weeks, respectively. Four participants with a history of frequent UTI in the prior 12 months did not have UTI in the 24 weeks of the study.. HA+CS was well tolerated. Recruitment was more difficult in early acute SCI; participants with chronic SCI were highly motivated to reduce UTI and manage self-administration without difficulty. Larger case-control or randomized controlled trials in patients with neurogenic bladder from SCI are warranted.. ClinicalTrials.gov identifier: NCT03945110. Topics: Chondroitin Sulfates; Humans; Hyaluronic Acid; Quality of Life; Spinal Cord Injuries; Urinary Tract Infections | 2023 |
Chondroitin sulfate expression around motoneurons changes after complete spinal transection of neonatal rats.
Hind limb locomotor activity spontaneously recovers after complete spinal transection (CST) in neonatal rats, but the mechanisms underlying the recovery are poorly understood. The perineuronal net (PNN) surrounding the neuronal cell bodies comprises an extracellular matrix that regulates neuronal plasticity during development. Here, we examined the expression of chondroitin sulfate (CS), a major component of the PNN, on motoneurons after CST in neonatal rats, and compared it with that in juvenile rats, in which hindlimb locomotor activity does not recover spontaneously. The spinal cord was transected at the mid-thoracic level in neonatal (postnatal day 5 [P5] and P10) and juvenile (P15 and P20) rats. Two weeks after CST, the percentage of motoneurons surrounded by chondroitin sulfate C (CS-C) - positive structures was significantly lower in rats with CST at P10 than in intact rats, and tended to be higher in rats with CST at P15 than in intact rats. The percentage of motoneurons with CS-A - positive structures was significantly lower in rats with CST at P15 than in intact rats. These findings suggest that CS-A and CS-C are differentially expressed in the PNNs in rats with CST. The decrease in CS-C - positive PNNs might facilitate the formation of new synaptic contacts to motoneurons, resulting in the recovery of the hindlimb locomotor activity in rats with CST during the neonatal period. Topics: Animals; Animals, Newborn; Axotomy; Chondroitin Sulfates; Extracellular Matrix; Female; Locomotion; Male; Motor Neurons; Nerve Regeneration; Rats; Rats, Wistar; Recovery of Function; Spinal Cord Injuries | 2022 |
Chondroitin 6-sulfate-binding peptides improve recovery in spinal cord-injured mice.
The role of glycosaminoglycan sulfation patterns, particularly in regard to scar formation and inhibition of neuritogenesis, has been mainly studied in cell culture with a focus on chondroitin 4-sulfate. In this study, we investigated chondroitin 6-sulfate (C6S) and found that it also inhibits neurite outgrowth of mouse cerebellar granule neurons in vitro. To examine whether the inhibitory activity of C6S could be neutralized, seven previously characterized high-affinity C6S-binding peptides were tested, among which three peptides neutralized the inhibitory functions of C6S. We further investigated these peptides in a mouse model of spinal cord injury, since upregulation of C6S expression in the glial scar following injury has been associated with reduced axonal regrowth and functional recovery. We here subjected mice to severe compression injury at thoracic levels T7-T9, immediately followed by inserting gelfoam patches soaked in C6S-binding peptides or in a control peptide. Application of C6S-binding peptides led to functional recovery after injury and prevented fibrotic glial scar formation, as seen by decreased activation of astrocytes and microglia/macrophages. Decreased expression of several lecticans and deposition of fibronectin at the site of injury were also observed. Application of C6S-binding peptides led to axonal regrowth and inhibited the C6S-mediated activation of RhoA/ROCK and decrease of PI3K-Akt-mTOR signaling pathways. Taken together, these results indicate that treatment with C6S-binding peptides improves functional recovery in a mouse model of spinal cord injury. Topics: Animals; Axons; Cells, Cultured; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Cicatrix; Disease Models, Animal; Gliosis; Glycogen Synthase Kinase 3 beta; Locomotion; Macrophages; Mice, Inbred C57BL; Microglia; Neuronal Outgrowth; Neurons; Peptides; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Recovery of Function; Remyelination; rho-Associated Kinases; rhoA GTP-Binding Protein; Spinal Cord Injuries; TOR Serine-Threonine Kinases | 2021 |
Inhibition of astrocytic differentiation of transplanted neural stem cells by chondroitin sulfate methacrylate hydrogels for the repair of injured spinal cord.
Neural stem cell (NSC) transplantation exerts a therapeutic effect on spinal cord injury (SCI) but is limited to an unregulated differentiation pattern by which NSCs preferentially differentiate into astrocytes, with relatively few neurons. It is well established that the increased NSC-derived astrocytes exhibit aberrant axonal sprouting associated with allodynia-like symptoms of the forepaws. Some strategies have been used to overcome this issue, such as regulation of major pathways, ex vivo gene transfer, and genetic overexpression. However, lack of efficiency, viral vector safety issues and the risk of tumorigenesis have hindered the clinical application of these treatments. Here, we show that astrocytic differentiation of NSCs in vitro and in vivo can be inhibited by encapsulation of cells in a three-dimensional chondroitin sulfate methacrylate (CSMA) hydrogel. When CSMA hydrogels were used to transplant NSCs, the combinatory implant promoted functional recovery and attenuated the hypersensitivity responses of the forepaws. Further analysis showed that transplantation of NSCs within CSMA hydrogels reduced injured cavity areas and promoted neurogenesis rather than fibroglial formation after graft implantation. Furthermore, the treatment prevented allodynia-related CGRP/GAP43-positive nociception due to fibers sprouting into inappropriate lamina regions. Taken together, these findings show that CSMA/NSCs combined transplantation helps prevent adverse side effects of NSCs treatment and promotes recovery of SCI. Topics: Animals; Astrocytes; Cell Differentiation; Cell Survival; Chondroitin Sulfates; Female; Hydrogels; Methacrylates; Neural Stem Cells; Neurogenesis; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries | 2019 |
Rapid and robust restoration of breathing long after spinal cord injury.
There exists an abundance of barriers that hinder functional recovery following spinal cord injury, especially at chronic stages. Here, we examine the rescue of breathing up to 1.5 years following cervical hemisection in the rat. In spite of complete hemidiaphragm paralysis, a single injection of chondroitinase ABC in the phrenic motor pool restored robust and persistent diaphragm function while improving neuromuscular junction anatomy. This treatment strategy was more effective when applied chronically than when assessed acutely after injury. The addition of intermittent hypoxia conditioning further strengthened the ventilatory response. However, in a sub-population of animals, this combination treatment caused excess serotonergic (5HT) axon sprouting leading to aberrant tonic activity in the diaphragm that could be mitigated via 5HT2 receptor blockade. Through unmasking of the continuing neuroplasticity that develops after injury, our treatment strategy ensured rapid and robust patterned respiratory recovery after a near lifetime of paralysis. Topics: Animals; Chondroitin Sulfates; Diaphragm; Extracellular Matrix; Female; Neuronal Plasticity; Paralysis; Rats, Sprague-Dawley; Receptors, Serotonin; Respiration; Serotonin; Spinal Cord Injuries | 2018 |
Chondroitin sulfates do not impede axonal regeneration in goldfish spinal cord.
Chondroitin sulfate proteoglycans produced in glial scar tissue are a major inhibitory factor for axonal regeneration after central nervous system injury in mammals. The inhibition is largely due to chondroitin sulfates, whose effects differ according to the sulfation pattern. In contrast to mammals, fish nerves spontaneously regenerate beyond the scar tissue after spinal cord injury, although the mechanisms that allow for axons to pass through the scar are unclear. Here, we used immunohistochemistry to examine the expression of two chondroitin sulfates with different sulfation variants at the lesion site in goldfish spinal cord. The intact spinal cord was immunoreactive for both chondroitin sulfate-A (CS-A) and chondroitin sulfate-C (CS-C), and CS-A immunoreactivity overlapped extensively with glial processes positive for glial fibrillary acidic protein. At 1week after inducing the spinal lesion, CS-A immunoreactivity was observed in the cell bodies and extracellular matrix, as well as in glial processes surrounding the lesion center. At 2weeks after the spinal lesion, regenerating axons entering the lesion center overtook the CS-A abundant area. In contrast, at 1week after lesion induction, CS-C immunoreactivity was significantly decreased, and at 2weeks after lesion induction, CS-C immunoreactivity was observed along the regenerating axons entering the lesion center. The present findings suggest that after spinal cord injury in goldfish, chondroitin sulfate proteoglycans are deposited in the extracellular matrix at the lesion site but do not form an impenetrable barrier to the growth of regenerating axons. Topics: Animals; Axons; Chondroitin Sulfates; Cicatrix; Fish Proteins; Glial Fibrillary Acidic Protein; Goldfish; Immunohistochemistry; Neuroglia; Spinal Cord; Spinal Cord Injuries; Spinal Cord Regeneration | 2017 |
Germline ablation of dermatan-4O-sulfotransferase1 reduces regeneration after mouse spinal cord injury.
Chondroitin/dermatan sulfate proteoglycans (CSPGs/DSPGs) are major components of the extracellular matrix. Their expression is generally upregulated after injuries to the adult mammalian central nervous system, which is known for its low ability to restore function after injury. Several studies support the view that CSPGs inhibit regeneration after injury, whereas the functions of DSPGs in injury paradigms are less certain. To characterize the functions of DSPGs in the presence of CSPGs, we studied young adult dermatan-4O-sulfotransferase1-deficient (Chst14(-/-)) mice, which express chondroitin sulfates (CSs), but not dermatan sulfates (DSs), to characterize the functional outcome after severe compression injury of the spinal cord. In comparison to their wild-type (Chst14(+/+)) littermates, regeneration was reduced in Chst14(-/-) mice. No differences between genotypes were seen in the size of spinal cords, numbers of microglia and astrocytes neither in intact nor injured spinal cords after injury. Monoaminergic innervation and re-innervation of the spinal cord caudal to the lesion site as well as expression levels of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) were similar in both genotypes, independent of whether they were injured and examined 6weeks after injury or not injured. These results suggest that, in contrast to CSPGs, DSPGs, being the products of Chst14 enzymatic activity, promote regeneration after injury of the adult mouse central nervous system. Topics: Animals; Behavior, Animal; Chondroitin Sulfates; Dermatan Sulfate; Disease Models, Animal; Mice; Motor Activity; Nerve Regeneration; Recovery of Function; Spinal Cord Injuries; Sulfotransferases | 2016 |
Intravenous Transplantation of Mesenchymal Progenitors Distribute Solely to the Lungs and Improve Outcomes in Cervical Spinal Cord Injury.
Cellular transplantation strategies utilizing intraspinal injection of mesenchymal progenitor cells (MPCs) have been reported as beneficial for spinal cord injuries. However, intraspinal injection is not only technically challenging, but requires invasive surgical procedures for patients. Therefore, we investigated the feasibility and potential benefits of noninvasive intravenous injection of MPCs in two models of cervical spinal cord injury, unilateral C5 contusion and complete unilateral C5 hemisection. MPCs isolated from green fluorescence protein (GFP)-luciferase transgenic mice compact bone (1 × 10(6) cells), or vehicle Hank's Buffered Saline Solution (HBSS), were intravenously injected via the tail vein at D1, D3, D7, D10, or D14. Transplanted MPCs were tracked via bioluminescence imaging. Live in vivo imaging data showed that intravenously injected MPCs accumulate in the lungs, confirmed by postmortem bioluminescence signal-irrespective of the time of injection or injury model. The results showed a rapid, positive modulation of the inflammatory response providing protection to the injured spinal cord tissue. Histological processing of the lungs showed GFP(+) cells evenly distributed around the alveoli. We propose that injected cells can act as cellular target decoys to an immune system primed by injury, thereby lessening the inflammatory response at the injury site. We also propose that intravenous injected MPCs modulate the immune system via the lungs through secreted immune mediators or contact interaction with peripheral organs. In conclusion, the timing of intravenous injection of MPCs is key to the success for improving function and tissue preservation following cervical spinal cord injury. Stem Cells 2016;34:1812-1825. Topics: Administration, Intravenous; Animals; Axons; Behavior, Animal; CD11b Antigen; Cervical Vertebrae; Chondroitin Sulfates; Contusions; Female; Immunohistochemistry; Luminescent Measurements; Lung; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Neovascularization, Physiologic; Neuroglia; Spinal Cord Injuries; Tissue Distribution; Treatment Outcome | 2016 |
Deletion of Crmp4 attenuates CSPG-induced inhibition of axonal growth and induces nociceptive recovery after spinal cord injury.
The capacity for regeneration in the injured adult mammalian central nervous system (CNS) is largely limited by potent inhibitory barriers. Chondroitin sulfate proteoglycans (CSPGs) are major inhibitors of axonal regeneration/sprouting and accumulate at lesion sites after CNS trauma. Despite extensive research during the two decades since their discovery, the molecular mechanisms remain elusive, including intracellular phosphorylation events. Collapsin response mediator protein 4 (CRMP4) is known to directly regulate cytoskeletal dynamics and neurite extension, while phosphorylated CRMP4 loses its binding affinity for cytoskeletal proteins. We have previously found that spinal cord injury (SCI) induces CRMP4 upregulation and phosphorylation and that CRMP4 knockout (Crmp4-/-) mice show behavioral recovery of locomotor function after SCI. However, the role of CRMP4 in the recovery of other forms of physiological function such as sensation remains largely unknown. We here have demonstrated CRMP4 involvement in CSPG-induced inhibitory signaling and nociceptive recovery in Crmp4-/- mice after SCI. We cultured dorsal root ganglion (DRG) neurons on CSPG-coated dishes; Crmp4 deletion overrode CSPG-induced inhibition of axon growth in vitro. CRMP4 levels were increased in DRGs in vivo after SCI. Crmp4-/- mice exhibited axonal growth of sensory neurons and recovery of nociceptive function after spinal transection. These results support Crmp4 deletion as a therapeutic target in the treatment of SCI. Topics: Animals; Axons; Cells, Cultured; Chondroitin Sulfates; Female; Ganglia, Spinal; Gene Deletion; Mice; Nerve Regeneration; Nerve Tissue Proteins; Neuronal Outgrowth; Nociception; Spinal Cord Injuries | 2016 |
Curcumin improves neural function after spinal cord injury by the joint inhibition of the intracellular and extracellular components of glial scar.
Spinal cord injury (SCI) is characterized by a high rate of disability and imposes a heavy burden on society and patients. SCI can activate glial cells and lead to swelling, hyperplasty, and reactive gliosis, which can severely reduce the space for nerve growth. Glial cells can secrete a large amount of extracellular inhibitory components, thus altering the microenvironment of axon growth. Both these factors seriously impede nerve regeneration. In the present study, we investigate whether curcumin (cur), a phytochemical compound with potent anti-inflammatory effect, plays a role in the repair of SCI.. We established a rat model of SCI and treated the animals with different concentrations of cur. Using behavioral assessment, immunohistochemistry, real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay, we detected the intracellular and extracellular components of glial scar and related cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor (NF)-κb, transforming growth factor (TGF)-β1, TGF-β2, and sex determining region Y-box (SOX)-9.. We found that cur inhibited the expression of proinflammatory cytokines, such as TNF-α, IL-1β, and NF-κb; reduced the expression of the intracellular components glial fibrillary acidic protein through anti-inflammation; and suppressed the reactive gliosis. Also, cur inhibited the generation of TGF-β1, TGF-β2, and SOX-9; decreased the deposition of chondroitin sulfate proteoglycan by inhibiting the transforming growth factors and transcription factor; and improved the microenvironment for nerve growth. Through the joint inhibition of the intracellular and extracellular components of glial scar, cur significantly reduced glial scar volume and improved the Basso, Beattie, and Bresnahan locomotor rating and axon growth.. Our data support a role for curcumin in promoting neural function recovery after SCI by the joint inhibition of the intracellular and extracellular components of glial scar, providing an important strategy for treating SCI. Topics: Animals; Antineoplastic Agents; Chondroitin Sulfates; Cicatrix; Curcumin; Cytokines; Extracellular Matrix; Female; Glial Fibrillary Acidic Protein; Gliosis; Locomotion; Phytotherapy; Plant Extracts; Random Allocation; Rats, Sprague-Dawley; Spinal Cord Injuries; Transcription Factors | 2015 |
A combination of keratan sulfate digestion and rehabilitation promotes anatomical plasticity after rat spinal cord injury.
Functional recovery after neuronal injuries relies on neuronal network reconstruction which involves many repair processes, such as sealing of injured axon ends, axon regeneration/sprouting, and construction and refinement of synaptic connections. Chondroitin sulfate (CS) is a major inhibitor of axon regeneration/sprouting. It has been reported that the combination of task-specific rehabilitation and CS-digestion is much more effective than either treatment alone with regard to the promotion of functional and anatomical plasticity for dexterity in acute and chronic spinal cord injury models. We previously reported that keratan sulfate (KS) is another inhibitor and has a potency equal to CS. Here, we compared the effects of KS- or CS-digestion plus rehabilitation on recovery from spinal cord injury. Keratanase II or chondroitinase ABC was locally administered at the lesion after spinal cord injury at C3/4. Task-specific rehabilitation training, i.e., a single pellet reaching task using a Whishaw apparatus, was done for 3 weeks before injury, and then again at 1-6 weeks after injury. The combination of KS-digestion and rehabilitation yielded a better rate of pellet removal than either KS-digestion alone or rehabilitation alone, although these differences were not statistically significant. The combination of CS-digestion and rehabilitation showed similar results. Strikingly, both KS-digestion/rehabilitation and CS-digestion/rehabilitation showed significant increases in neurite growth in vivo as estimated by 5-hydroxytryptamine and GAP43 staining. Thus, KS-digestion and rehabilitation exerted a synergistic effect on anatomical plasticity, and this effect was comparable with that of CS-digestion/rehabilitation. KS-digestion might widen the therapeutic window of spinal cord injury if combined with rehabilitation. Topics: Animals; Chondroitin Sulfates; Female; Keratan Sulfate; Neuronal Plasticity; Rats, Sprague-Dawley; Spinal Cord Injuries | 2015 |
Long-term characterization of axon regeneration and matrix changes using multiple channel bridges for spinal cord regeneration.
Spinal cord injury (SCI) results in loss of sensory and motor function below the level of injury and has limited available therapies. The host response to SCI is typified by limited endogenous repair, and biomaterial bridges offer the potential to alter the microenvironment to promote regeneration. Porous multiple channel bridges implanted into the injury provide stability to limit secondary damage and support cell infiltration that limits cavity formation. At the same time, the channels provide a path that physically directs axon growth across the injury. Using a rat spinal cord hemisection injury model, we investigated the dynamics of axon growth, myelination, and scar formation within and around the bridge in vivo for 6 months, at which time the bridge has fully degraded. Axons grew into and through the channels, and the density increased overtime, resulting in the greatest axon density at 6 months postimplantation, despite complete degradation of the bridge by that time point. Furthermore, the persistence of these axons contrasts with reports of axonal dieback in other models and is consistent with axon stability resulting from some degree of connectivity. Immunostaining of axons revealed both motor and sensory origins of the axons found in the channels of the bridge. Extensive myelination was observed throughout the bridge at 6 months, with centrally located and peripheral channels seemingly myelinated by oligodendrocytes and Schwann cells, respectively. Chondroitin sulfate proteoglycan deposition was restricted to the edges of the bridge, was greatest at 1 week, and significantly decreased by 6 weeks. The dynamics of collagen I and IV, laminin, and fibronectin deposition varied with time. These studies demonstrate that the bridge structure can support substantial long-term axon growth and myelination with limited scar formation. Topics: Acetylcholinesterase; Animals; Axons; Calcitonin Gene-Related Peptide; Chondroitin Sulfates; Collagen Type I; Collagen Type IV; Extracellular Matrix; Female; Fibronectins; Laminin; Myelin Sheath; Rats; Rats, Long-Evans; Spinal Cord Injuries; Spinal Cord Regeneration; Time Factors | 2014 |
Extracellular matrix-regulated neural differentiation of human multipotent marrow progenitor cells enhances functional recovery after spinal cord injury.
Recent advanced studies have demonstrated that cytokines and extracellular matrix (ECM) could trigger various types of neural differentiation. However, the efficacy of differentiation and in vivo transplantation has not yet thoroughly been investigated.. To highlight the current understanding of the effects of ECM on neural differentiation of human bone marrow-derived multipotent progenitor cells (MPCs), regarding state-of-art cure for the animal with acute spinal cord injury (SCI), and explore future treatments aimed at neural repair.. A selective overview of the literature pertaining to the neural differentiation of the MSCs and experimental animals aimed at improved repair of SCI.. Extracellular matrix proteins, tenascin-cytotactin (TN-C), tenascin-restrictin (TN-R), and chondroitin sulfate (CS), with the cytokines, nerve growth factor (NGF)/brain-derived neurotrophic factor (BDNF)/retinoic acid (RA) (NBR), were incorporated to induce transdifferentiation of human MPCs. Cells were treated with NBR for 7 days, and then TN-C, TN-R, or CS was added for 2 days. The medium was changed every 2 days. Twenty-four animals were randomly assigned to four groups with six animals in each group: one experimental and three controls. Animals received two (bilateral) injections of vehicle, MPCs, NBR-induced MPCs, or NBR/TN-C-induced MPCs into the lesion sites after SCI. Functional assessment was measured using the Basso, Beattie, and Bresnahan locomotor rating score. Data were analyzed using analysis of variance followed by Student-Newman-Keuls (SNK) post hoc tests.. Results showed that MPCs with the transdifferentiation of human MPCs to neurons were associated with increased messenger-RNA (mRNA) expression of neuronal markers including nestin, microtubule-associated protein (MAP) 2, glial fibrillary acidic protein, βIII tubulin, and NGF. Greater amounts of neuronal morphology appeared in cultures incorporated with TN-C and TN-R than those with CS. The addition of TN-C enhanced mRNA expressions of MAP2, βIII tubulin, and NGF, whereas TN-R did not significantly change. Conversely, CS exposure decreased MAP2, βIII tubulin, and NGF expressions. The TN-C-treated MSCs significantly and functionally repaired SCI-induced rats at Day 42. Present results indicate that ECM components, such as tenascins and CS in addition to cytokines, may play functional roles in regulating neurogenesis by human MPCs.. These findings suggest that the combined use of TN-C, NBR, and human MPCs offers a new feasible method for nerve repair. Topics: Animals; Brain-Derived Neurotrophic Factor; Cell Transdifferentiation; Chondroitin Sulfates; Extracellular Matrix; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Nerve Growth Factor; Neurons; Rats; Recovery of Function; Spinal Cord Injuries; Tenascin | 2014 |
Evaluation of the effect of tranilast on rats with spinal cord injury.
Glial and fibrotic scars inhibit neural regeneration after spinal cord injury (SCI). N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor β, alleviates allergic reactions, and decreases hypertrophic skin scars. We evaluated its ability to improve motor function and inhibit the spread of tissue damage in rats with SCI.. Rats with SCI were divided into groups that received tranilast (30 mg/[kg · day]) by intravenous administration (group IV), tranilast (200mg/[kg · day]) by oral administration (group OR), and saline injections (control). Motor functions were assessed by determining Basso, Beattie, and Bresnahan (BBB) scores and %grip tests for 8 weeks after SCI. Histological evaluation of ionized calcium binding adaptor molecule 1 (Iba1) at 1 week after SCI and glial fibrillary acidic protein (GFAP), fibronectin, and chondroitin sulfate (CS) at week 8 was performed.. Motor function recovery, BBB score, and the %grip test were significantly higher in the tranilast-treated groups than in the control group. At week 1 after SCI, inflammatory-cell invasion was more severe and Iba1 expression was significantly higher in the control group. At week 8, although the number of GFAP-positive cells increased greatly from the impaction site to the proximal and distal sites in the control group, these cells were confined around a cavity in the tranilast-treated groups. GFAP distribution coincided with that of fibronectin. Anti-CS antibody level in the tranilast-treated groups was significantly lower than that in the control group.. Tranilast inhibits inflammation in the acute phase of SCI and reduces glial and fibrotic scars and could present a new method for treating SCI. Topics: Animals; Calcium-Binding Proteins; Chondroitin Sulfates; Disease Models, Animal; Fibronectins; Glial Fibrillary Acidic Protein; Microfilament Proteins; Motor Activity; ortho-Aminobenzoates; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord; Spinal Cord Injuries | 2014 |
Arylsulfatase B improves locomotor function after mouse spinal cord injury.
Bacterial chondroitinase ABC (ChaseABC) has been used to remove the inhibitory chondroitin sulfate chains from chondroitin sulfate proteoglycans to improve regeneration after rodent spinal cord injury. We hypothesized that the mammalian enzyme arylsulfatase B (ARSB) would also enhance recovery after mouse spinal cord injury. Application of the mammalian enzyme would be an attractive alternative to ChaseABC because of its more robust chemical stability and reduced immunogenicity. A one-time injection of human ARSB into injured mouse spinal cord eliminated immunoreactivity for chondroitin sulfates within five days, and up to 9 weeks after injury. After a moderate spinal cord injury, we observed improvements of locomotor recovery assessed by the Basso Mouse Scale (BMS) in ARSB treated mice, compared to the buffer-treated control group, at 6 weeks after injection. After a severe spinal cord injury, mice injected with equivalent units of ARSB or ChaseABC improved similarly and both groups achieved significantly more locomotor recovery than the buffer-treated control mice. Serotonin and tyrosine hydroxylase immunoreactive axons were more extensively present in mouse spinal cords treated with ARSB and ChaseABC, and the immunoreactive axons penetrated further beyond the injury site in ARSB or ChaseABC treated mice than in control mice. These results indicate that mammalian ARSB improves functional recovery after CNS injury. The structural/molecular mechanisms underlying the observed functional improvement remain to be elucidated. Topics: Animals; Bacterial Proteins; Chondroitin ABC Lyase; Chondroitin Sulfates; Disease Models, Animal; Female; Humans; Locomotion; Mice; N-Acetylgalactosamine-4-Sulfatase; Recombinant Proteins; Recovery of Function; Spinal Cord Injuries | 2013 |
Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury.
Extracellular factors that inhibit axon growth and intrinsic factors that promote it affect neural regeneration. Therapies targeting any single gene have not yet simultaneously optimized both types of factors. Chondroitin sulphate (CS), a glycosaminoglycan, is the most abundant extracellular inhibitor of axon growth. Here we show that mice carrying a gene knockout for CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, recover more completely from spinal cord injury than wild-type mice and even chondroitinase ABC-treated mice. Notably, synthesis of heparan sulphate (HS), a glycosaminoglycan promoting axonal growth, is also upregulated in TI knockout mice because HS-synthesis enzymes are induced in the mutant neurons. Moreover, chondroitinase ABC treatment never induces HS upregulation. Taken together, our results indicate that regulation of a single gene, T1, mediates excellent recovery from spinal cord injury by optimizing counteracting effectors of axon regeneration--an extracellular inhibitor of CS and intrinsic promoters, namely, HS-synthesis enzymes. Topics: Animals; Chondroitin Sulfates; Gene Expression Regulation, Enzymologic; Mice; Mice, Knockout; N-Acetylgalactosaminyltransferases; Spinal Cord Injuries | 2013 |
Induction of angiopoietin-2 after spinal cord injury.
Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) have opposing effects on blood vessels, with Ang-2 being mainly induced during the endothelial barrier breakdown. It is known that spinal cord injury (SCI) induces lasting decreases in Ang-1 levels, underlying endothelial barrier disruption, but the expression of Ang-2 in spinal cord injury has not been studied. We characterized Ang-2 after SCI using a clinically relevant rat model of contusion SCI. We found that SCI induces marked and persistent upregulation of Ang-2 (up to 10 weeks after SCI), which does not reflect well-characterized temporal profile of the blood-spinal cord barrier (BSCB) breakdown after SCI, and thus suggests other role(s) for Ang-2 in injured spinal cords. Furthermore, we also found that higher Ang-2 levels were associated with more successful locomotor recovery after SCI, both in SCI rats with markedly better spontaneous motor recovery and in SCI rats receiving a neuroprotective pharmacological intervention (amiloride), suggesting a beneficial role for Ang-2 in injured spinal cords. Immunocytochemical analyses revealed that Ang-2 was not induced in endothelial cells, but in perivascular and non-vascular cells labeled with glial fibrillary acidic protein (GFAP) or with chondroitin sulfate proteoglycan (NG2). Therefore, it is unlikely that induction of Ang-2 contributes to vascular dysfunction underlying functional impairment after SCI, but rather that it contributes to the beneficial pro-angiogenic and/or gliogenic processes underlying recovery processes after SCI. Topics: Amiloride; Angiopoietin-1; Angiopoietin-2; Animals; Blood Vessels; Blood-Brain Barrier; Blotting, Western; Chondroitin Sulfates; Diuretics; Electrophoresis, Polyacrylamide Gel; Fluorescent Antibody Technique; Glial Fibrillary Acidic Protein; Immunohistochemistry; Male; Microscopy, Confocal; Motor Activity; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord; Spinal Cord Injuries | 2012 |
Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice.
Chondroitin sulphate proteoglycans (CSPGs) are extracellular matrix molecules whose inhibitory activity is attenuated by the enzyme chondroitinase ABC (ChABC). Here we assess whether CSPG degradation can promote compensatory sprouting of the intact corticospinal tract (CST) following unilateral injury and restore function to the denervated forelimb. Adult C57BL/6 mice underwent unilateral pyramidotomy and treatment with either ChABC or a vehicle control. Significant impairments in forepaw symmetry were observed following pyramidotomy, with injured mice preferentially using their intact paw during spontaneous vertical exploration of a cylinder. No recovery on this task was observed in vehicle-treated mice. However, ChABC-treated mice showed a marked recovery of function, with forelimb symmetry fully restored by 5 weeks post-injury. Functional recovery was associated with robust sprouting of the uninjured CST, with numerous axons observed crossing the midline in the brainstem and spinal cord and terminating in denervated grey matter. CST fibres in the denervated side of the spinal cord following ChABC treatment were closely associated with the synaptic marker vGlut1. Immunohistochemical assessment of chondroitin-4-sulphate revealed that CSPGs were heavily digested around lamina X, alongside midline crossing axons and in grey matter regions where sprouting axons and reduced peri-neuronal net staining was observed. Thus, we demonstrate that CSPG degradation promotes midline crossing and reinnervation of denervated target regions by intact CST axons and leads to restored function in the denervated forepaw. Enhancing compensatory sprouting using ChABC provides a route to restore function that could be applied to disorders such as spinal cord injury and stroke. Topics: Animals; Axons; Chondroitin ABC Lyase; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Denervation; Forelimb; Male; Mice; Mice, Inbred C57BL; Pyramidal Tracts; Spinal Cord Injuries; Spinal Cord Regeneration | 2012 |
N-acetylglucosamine 6-O-sulfotransferase-1-deficient mice show better functional recovery after spinal cord injury.
Neurons in the adult CNS do not spontaneously regenerate after injuries. The glycosaminoglycan keratan sulfate is induced after spinal cord injury, but its biological significance is not well understood. Here we investigated the role of keratan sulfate in functional recovery after spinal cord injury, using mice deficient in N-acetylglucosamine 6-O-sulfotransferase-1 that lack 5D4-reactive keratan sulfate in the CNS. We made contusion injuries at the 10th thoracic level. Expressions of N-acetylglucosamine 6-O-sulfotransferase-1 and keratan sulfate were induced after injury in wild-type mice, but not in the deficient mice. The wild-type and deficient mice showed similar degrees of chondroitin sulfate induction and of CD11b-positive inflammatory cell recruitment. However, motor function recovery, as assessed by the footfall test, footprint test, and Basso mouse scale locomotor scoring, was significantly better in the deficient mice. Moreover, the deficient mice showed a restoration of neuromuscular system function below the lesion after electrical stimulation at the occipito-cervical area. In addition, axonal regrowth of both the corticospinal and raphespinal tracts was promoted in the deficient mice. In vitro assays using primary cerebellar granule neurons demonstrated that keratan sulfate proteoglycans were required for the proteoglycan-mediated inhibition of neurite outgrowth. These data collectively indicate that keratan sulfate expression is closely associated with functional disturbance after spinal cord injury. N-acetylglucosamine 6-O-sulfotransferase-1-deficient mice are a good model to investigate the roles of keratan sulfate in the CNS. Topics: Animals; Axons; Brain; Carbohydrate Sulfotransferases; CD11b Antigen; Cells, Cultured; Chondroitin Sulfates; Female; Keratan Sulfate; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Nerve Regeneration; Neural Pathways; Neurites; Neuromuscular Junction; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries; Sulfotransferases | 2010 |
PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration.
Chondroitin sulfate proteoglycans (CSPGs) present a barrier to axon regeneration. However, no specific receptor for the inhibitory effect of CSPGs has been identified. We showed that a transmembrane protein tyrosine phosphatase, PTPsigma, binds with high affinity to neural CSPGs. Binding involves the chondroitin sulfate chains and a specific site on the first immunoglobulin-like domain of PTPsigma. In culture, PTPsigma(-/-) neurons show reduced inhibition by CSPG. A PTPsigma fusion protein probe can detect cognate ligands that are up-regulated specifically at neural lesion sites. After spinal cord injury, PTPsigma gene disruption enhanced the ability of axons to penetrate regions containing CSPG. These results indicate that PTPsigma can act as a receptor for CSPGs and may provide new therapeutic approaches to neural regeneration. Topics: Aggrecans; Animals; Astrocytes; Axons; Binding Sites; Cells, Cultured; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Female; Ganglia, Spinal; Ligands; Mice; Nerve Regeneration; Nerve Tissue Proteins; Neurites; Neurocan; Neurons; Protein Binding; Protein Interaction Domains and Motifs; Proteoglycans; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Recombinant Fusion Proteins; Spinal Cord; Spinal Cord Injuries | 2009 |
Chondroitin-4-sulfation negatively regulates axonal guidance and growth.
Glycosaminoglycan (GAG) side chains endow extracellular matrix proteoglycans with diversity and complexity based upon the length, composition and charge distribution of the polysaccharide chain. Using cultured primary neurons, we show that specific sulfation in the GAG chains of chondroitin sulfate mediates neuronal guidance cues and axonal growth inhibition. Chondroitin-4-sulfate (CS-A), but not chondroitin-6-sulfate (CS-C), exhibits a strong negative guidance cue to mouse cerebellar granule neurons. Enzymatic and gene-based manipulations of 4-sulfation in the GAG side chains alter their ability to direct growing axons. Furthermore, 4-sulfated chondroitin sulfate GAG chains are rapidly and significantly increased in regions that do not support axonal regeneration proximal to spinal cord lesions in mice. Thus, our findings show that specific sulfation along the carbohydrate backbone carries instructions to regulate neuronal function. Topics: Animals; Astrocytes; Axons; Cell Movement; Cells, Cultured; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Glycosaminoglycans; Mice; Mice, Inbred C57BL; Neurons; RNA, Small Interfering; Spinal Cord Injuries; Sulfates; Sulfotransferases | 2008 |
Antisense vimentin cDNA combined with chondroitinase ABC reduces glial scar and cystic cavity formation following spinal cord injury in rats.
The formation of glial scar and cystic cavities restricts axon regeneration after spinal cord injury. Chondroitin sulphate proteoglycans (CSPGs) are regarded as the prominent inhibitory molecules in the glial scar, and their inhibitory effects may be abolished in part by chondroitinase ABC (ChABC), which can digest CSPGs. CSPGs are secreted mostly by reactive astrocytes, which form dense scar tissues. The intermediate filament protein vimentin underpins the cytoskeleton of reactive astrocytes. Previously we have shown that retroviruses carrying full-length antisense vimentin cDNA reduce reactive gliosis. Here we administered both antisense vimentin cDNA and ChABC to hemisected rat spinal cords. Using RT-PCR, Western blotting and immunohistochemistry, we found that the combined treatment reduced the formation of glial scar and cystic cavities through degrading CSPGs molecules and inhibiting intermediate filament proteins. The modified intra- and extra-cellular architecture may alter the physical and biochemical characteristics of the scar, and the combined therapy might be used to inhibit glial scar formation. Topics: Animals; Chondroitin ABC Lyase; Chondroitin Sulfates; Cicatrix; Cysts; DNA, Antisense; DNA, Complementary; Genetic Therapy; Nerve Regeneration; Neuroglia; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Vimentin | 2008 |
Single, high-dose intraspinal injection of chondroitinase reduces glycosaminoglycans in injured spinal cord and promotes corticospinal axonal regrowth after hemisection but not contusion.
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. Topics: Animals; Axons; Chondroitin ABC Lyase; Chondroitin Sulfates; Dose-Response Relationship, Drug; Female; Injections, Spinal; Nerve Regeneration; Pyramidal Tracts; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Time Factors | 2008 |
Poly (D,L-lactic acid) macroporous guidance scaffolds seeded with Schwann cells genetically modified to secrete a bi-functional neurotrophin implanted in the completely transected adult rat thoracic spinal cord.
Freeze-dried poly(D,L-lactic acid) macroporous scaffold filled with a fibrin solution containing Schwann cells (SCs) lentivirally transduced to produce and secrete D15A, a bi-functional neurotrophin with brain-derived neurotrophic factor and neurotrophin-3 activity, and to express green fluorescent protein (GFP) were implanted in the completely transected adult rat thoracic spinal cord. Control rats were similarly injured and then implanted with scaffolds containing the fibrin solution with SCs lentivirally transduced to produce express GFP only or with the fibrin solution only. Transgene production and biological activity in vitro, SC survival within the scaffold in vitro and in vivo, scaffold integration, axonal regeneration and myelination, and hind limb motor function were analyzed at 1, 2, and 6 weeks after implantation. In vitro, lentivirally transduced SCs produced 87.5 ng/24 h/10(6) cells of D15A as measured by neurotrophin-3 activity in ELISA. The secreted D15A was biologically active as evidenced by its promotion of neurite outgrowth of dorsal root ganglion neurons in culture. In vitro, SCs expressing GFP were present in the scaffolds for up to 6 h, the end of a typical surgery session. Implantation of SC-seeded scaffolds caused modest loss of spinal nervous tissue. Reactive astrocytes and chondroitin sulfate glycosaminoglycans were present in spinal tissue adjacent to the scaffold. Vascularization of the scaffold was ongoing at 1 week post-implantation. There were no apparent differences in scaffold integration and blood vessel formation between groups. A decreasing number of implanted (GFP-positive) SCs were found within the scaffold during the first 3 days after implantation. Apoptosis was identified as one of the mechanisms of cell death. At 1 week and later time points after implantation, few of the implanted SCs were present in the scaffold. Neurofilament-positive axons were found in the scaffold. At 6 weeks post-grafting, myelinated axons were observed within and at the external surface of the scaffold. Axons did not grow from the scaffold into the caudal cord. All groups demonstrated a similar improvement of hind limb motor function. Our findings demonstrated that few seeded SCs survived in vivo, which could account for the modest axonal regeneration response into and across the scaffold. For the development of SC-seeded macroporous scaffolds that effectively promote axonal regeneration in the injured spinal cord, the survival and/or tot Topics: Animals; Axons; Blood Vessels; Cell Enlargement; Cell Survival; Chondroitin Sulfates; Culture Media, Conditioned; Female; Ganglia, Spinal; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Guided Tissue Regeneration; Hindlimb; Implants, Experimental; Lactic Acid; Neovascularization, Physiologic; Nerve Fibers, Myelinated; Nerve Growth Factors; Nerve Regeneration; Neurotrophin 3; Polyesters; Polymers; Rats; Rats, Inbred F344; Schwann Cells; Spinal Cord; Spinal Cord Injuries; Thoracic Vertebrae; Transfection | 2006 |
Embryonic radial glia bridge spinal cord lesions and promote functional recovery following spinal cord injury.
Radial glial cells are neural stem cells (NSC) that are transiently found in the developing CNS. To study radial glia, we isolated clones following immortalization of E13.5 GFP rat neurospheres with v-myc. Clone RG3.6 exhibits polarized morphology and expresses the radial glial markers nestin and brain lipid binding protein. Both NSC and RG3.6 cells migrated extensively in the adult spinal cord. However, RG3.6 cells differentiated into astroglia slower than NSC, suggesting that immortalization can delay differentiation of radial glia. Following spinal cord contusion, implanted RG3.6 cells migrated widely in the contusion site and into spared white matter where they exhibited a highly polarized morphology. When injected immediately after injury, RG3.6 cells formed cellular bridges surrounding spinal cord lesion sites and extending into spared white matter regions in contrast to GFP fibroblasts that remained in the lesion site. Behavioral analysis indicated higher BBB scores in rats injected with RG3.6 cells than rats injected with fibroblasts or medium as early as 1 week after injury. Spinal cords transplanted with RG3.6 cells or dermal fibroblasts exhibited little accumulation of chondroitin sulfate proteoglycans (CSPG) including NG2 proteoglycans that are known to inhibit axonal growth. Reduced levels of CSPG were accompanied by little accumulation in the injury site of activated macrophages, which are a major source of CSPG. However, increased staining and organization of neurofilaments were found in injured rats transplanted with RG3.6 cells suggesting neuroprotection or regrowth. The combined results indicate that acutely transplanted radial glia can migrate to form bridges across spinal cord lesions in vivo and promote functional recovery following spinal cord injury by protecting against macrophages and secondary damage. Topics: Animals; Antigens; Behavior, Animal; Carrier Proteins; Cell Differentiation; Cells, Cultured; Chondroitin Sulfates; Clone Cells; Ectodysplasins; Embryo, Mammalian; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Female; Fibroblasts; Fluorescent Antibody Technique; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Indoles; Intermediate Filament Proteins; Male; Membrane Proteins; Motor Activity; Nerve Tissue Proteins; Nestin; Neurofilament Proteins; Neuroglia; Prosencephalon; Proteoglycans; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries; Stem Cell Transplantation; Stem Cells; Time Factors; Tubulin | 2005 |
Basic fibroblast growth factor promotes neuronal survival but not behavioral recovery in the transected and Schwann cell implanted rat thoracic spinal cord.
It was investigated whether the addition of basic fibroblast growth factor (FGF-2) enhances the efficacy of a Schwann cell (SC) bridge to repair the transected spinal cord by assessing tissue sparing and neuronal survival near the graft-cord interfaces, axonal regeneration and myelination in the graft, and behavioral recovery up to 12 weeks post-grafting. Experimental animals received a bridge of SCs within fibrin containing 1 microg of FGF-2; control animals received a SC implant without FGF-2. Sparing of tissue in a 2.5-mm-long segment near the graft-cord borders was 69% in the rostral and 52% in the caudal cord at 6 weeks post-grafting, not significantly different from the control group. With FGF-2, survival of NeuN-positive cells was increased in the rostral cord: 24.4%, 20.4%, and 17.2% of the number of positive cells in the uninjured cord compared to 13.5%, 9.1%, and 8.9% in controls at 3, 6, and 12 weeks post-grafting, respectively. Similarly, in the caudal cord, survival of NeuN-positive cells was increased with FGF-2: 19.3%, 16.8%, and 14.5% compared to 10.8%, 5.6%, and 6.1% in controls. The staining intensity of glial fibrillary acidic protein was significantly higher at the interfaces of both cord stumps at 3 weeks with SC/FGF-2 grafts; chondroitin sulfate proteoglycan (CS-56) staining was more intense in the rostral cord but only at 6 weeks. Blood vessels in the FGF-2 grafts were larger and less regular in shape than those in control grafts. Axonal growth into the bridge was not improved by the addition of FGF-2. Retrogradely traced neurons were not found rostral to the implant, indicating that axons had not grown a few mm into the caudal spinal tissue. Recovery of hind limb function was similar in both groups. Despite the neuroprotective effects of FGF-2, improved effects on axonal regeneration and functional recovery were not observed. Topics: Animals; Behavior, Animal; Cell Transplantation; Chondroitin Sulfates; Female; Fibroblast Growth Factor 2; Glial Fibrillary Acidic Protein; Immunohistochemistry; Microscopy, Electron, Transmission; Nerve Regeneration; Neurons; Rats; Rats, Inbred F344; Schwann Cells; Spinal Cord Injuries; Thoracic Vertebrae | 2004 |
Axonal regeneration of Clarke's neurons beyond the spinal cord injury scar after treatment with chondroitinase ABC.
We have previously demonstrated that enzymatic digestion of chondroitin sulfate proteoglycan (CSPG) at the scar promotes the axonal regrowth of Clarke's nucleus (CN) neurons into an implanted peripheral nerve graft after hemisection of the spinal cord. The present study examined whether degradation of CSPG using chondroitinase ABC promoted the regeneration of CN neurons through the scar into the rostral spinal cord in neonatal and adult rats. Following hemisection of the spinal cord at T11, either vehicle or chondroitinase ABC was applied onto the lesion site. The postoperative survival periods were 2 and 4 weeks. The regenerated CN neurons were retrogradely labeled by Fluoro-Gold injected at spinal cord level C7. In the sham group, there was no regeneration of injured CN neurons in both neonatal and adult rats. Treatment with 2.5 unit/ml chondroitinase ABC in neonates resulted in 11.8 and 8.3% of the injured CN neurons regenerated into the rostral spinal cord at 2 and 4 weeks, respectively. In adults, 9.4 and 12.3%, at 2 and 4 weeks, respectively, of the injured CN neurons regenerated their axons to the rostral spinal cord. The immunoreactivity for the carbohydrate epitope of CSPG was dramatically decreased around the lesion site after treatment with chondroitinase ABC compared to sham control in both neonatal and adult animals. Our results show that axonal regeneration in the spinal cord can be promoted by degradation of CSPG with chondroitinase ABC. This result further suggests that CSPG is inhibitory to the regeneration of neurons in the spinal cord after traumatic injury. Topics: Age Factors; Animals; Animals, Newborn; Axons; Chondroitin ABC Lyase; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Cicatrix; Disease Models, Animal; Female; Immunohistochemistry; Nerve Regeneration; Neurons; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries | 2003 |
Chondroitinase ABC promotes axonal regeneration of Clarke's neurons after spinal cord injury.
We examined whether enzymatic digestion of chondroitin sulfate (CS) promoted the axonal regeneration of neurons in Clarke's nucleus (CN) into a peripheral nerve (PN) graft following injury of the spinal cord. After hemisection at T11, a segment of PN graft was implanted at the lesion site. Either vehicle, brain-derived neurotrophic factor (BDNF) or chondroitinase ABC was applied at the implantation site. The postoperative survival period was 4 weeks. Treatment with vehicle or BDNF did not promote the axonal regeneration of CN neurons into the PN graft. Application of 2.5 unit/ml chondroitinase ABC resulted in a significant increase (12.8%) in the number of regenerated CN neurons. Double labeling with Fluoro-Gold and NADPH-diaphorase histochemistry showed that the regenerated CN neurons did not express nitric oxide synthase (NOS). Our results suggest that CS is inhibitory to the regeneration of CN neurons following injury of the spinal cord. Topics: Animals; Axons; Brain-Derived Neurotrophic Factor; Chondroitin ABC Lyase; Chondroitin Sulfates; Denervation; Dose-Response Relationship, Drug; Female; Fluorescent Dyes; Immunohistochemistry; NADPH Dehydrogenase; Nerve Regeneration; Nitric Oxide Synthase; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Spinocerebellar Tracts; Stilbamidines | 2000 |
Evaluation of two cross-linked collagen gels implanted in the transected spinal cord.
In previous experiments, we have shown that spinal axons grow into a collagen matrix implanted between the stumps of a transected spinal cord. However, the matrix became denatured after 2 to 3 months. To improve the stability and the durability of the collagen gel implants, collagen was coprecipitated with chondroitin-6-sulfate (C-6-S) or chemically cross-linked with carbodiimide (CD). The spinal cords were taken out after 3 days, 1, 3, or 6 months and analyzed using different histological and tracing techniques. The cross-linked collagen matrices underwent major structural changes. Cross-linking treatments improved the stability of collagen implants which withstood at least 6 months. Axons revealed with DiI or silver staining crossed the proximal interface and grew into the bioimplants. Some axons were also followed across the distal bioimplant-spinal interface in DiI treated tissues. This study suggests that cross-linking the collagen hydrogel has improved the mechanical properties of the matrix, modified the normal scarring process, and favored axonal regeneration. Topics: Animals; Axons; Carbodiimides; Chemical Precipitation; Chondroitin Sulfates; Collagen; Cross-Linking Reagents; Female; Gels; Nerve Regeneration; Prostheses and Implants; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Wound Healing | 1993 |