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1.  Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice 
The Journal of Clinical Investigation  2011;121(11):4332-4347.
Although peripheral nerves can regenerate after injury, proximal nerve injury in humans results in minimal restoration of motor function. One possible explanation for this is that injury-induced axonal growth is too slow. Heat shock protein 27 (Hsp27) is a regeneration-associated protein that accelerates axonal growth in vitro. Here, we have shown that it can also do this in mice after peripheral nerve injury. While rapid motor and sensory recovery occurred in mice after a sciatic nerve crush injury, there was little return of motor function after sciatic nerve transection, because of the delay in motor axons reaching their target. This was not due to a failure of axonal growth, because injured motor axons eventually fully re-extended into muscles and sensory function returned; rather, it resulted from a lack of motor end plate reinnervation. Tg mice expressing high levels of Hsp27 demonstrated enhanced restoration of motor function after nerve transection/resuture by enabling motor synapse reinnervation, but only within 5 weeks of injury. In humans with peripheral nerve injuries, shorter wait times to decompression surgery led to improved functional recovery, and, while a return of sensation occurred in all patients, motor recovery was limited. Thus, absence of motor recovery after nerve damage may result from a failure of synapse reformation after prolonged denervation rather than a failure of axonal growth.
PMCID: PMC3223863  PMID: 21965333
2.  Peripheral nerve regeneration is delayed in neuropilin 2-deficient mice 
Journal of neuroscience research  2008;86(14):3163-3169.
Peripheral nerve transection or crush induces expression of class 3 semaphorins by epineurial and perineurial cells at the injury site, and of the neuropilins, neuropilin-1 and neuropilin-2, by Schwann and perineurial cells in the nerve segment distal to the injury. Neuropilin-dependent class 3 semaphorin signaling guides axons during neural development, but the significance of this signaling system for regeneration of adult peripheral nerves is not known. To test the hypothesis that neuropilin-2 facilitates peripheral nerve axonal regeneration, we crushed sciatic nerves of adult neuropilin-2 deficient and littermate control mice. Axonal regeneration through the crush site and into the distal nerve segment, repression by the regenerating axons of Schwann cell p75 neurotrophin receptor expression, remyelination of the regenerating axons, and recovery of normal gait were all significantly slower in the neuropilin-2 deficient than control mice. Thus, neuropilin-2 facilitates peripheral nerve axonal regeneration.
PMCID: PMC2574585  PMID: 18615644
peripheral nervous system; axons; Schwann cells; semaphorins; sciatic nerve
3.  Acetyl salicylic acid augments functional recovery following sciatic nerve crush in mice 
Cyclin-dependent kinase 5 (CDK-5) appears to play a significant role in peripheral nerve regeneration as CDK-5 inhibition retards nerve regeneration following nerve crush. Anti-inflammatory drug acetyl salicylic acid elevates CDK-5 and reduces ischemia – reperfusion injury in cultured neurons. In this study we have evaluated the effect of acetyl salicylic acid on functional recovery following sciatic nerve crush in mice. Eighteen Swiss albino mice underwent unilateral sciatic nerve crush. Test animals received acetyl salicylic acid (100 mg/kg/day, n = 6 or 50 mg/kg/day, n = 6) and control animals (n = 6) received normal saline for 14 days following surgery. Functional recovery was assessed with improvement in Sciatic Function Index, nociception and gait. In comparison with normal saline treatment, acetyl salicylic acid (100 mg/kg/day) significantly improved functional recovery following sciatic nerve crush. Anti-inflammatory drug acetyl salicylic acid appears to be a promising agent for treating peripheral nerve injuries and hence elucidation of its neuroprotective pathways is necessary.
PMCID: PMC1802865  PMID: 17274829
4.  Celecoxib accelerates functional recovery after sciatic nerve crush in the rat 
The inflammatory response appears to be essential in the modulation of the degeneration and regeneration process after peripheral nerve injury. In injured nerves, cyclooxygenase-2 (COX-2) is strongly upregulated around the injury site, possibly playing a role in the regulation of the inflammatory response. In this study we investigated the effect of celecoxib, a COX-2 inhibitor, on functional recovery after sciatic nerve crush in rats. Unilateral sciatic nerve crush injury was performed on 10 male Wistar rats. Animals on the experimental group (n = 5) received celecoxib (10 mg/kg ip) immediately before the crush injury and daily for 7 days after the injury. Control group (n = 5) received normal saline at equal regimen. A sham group (n = 5), where sciatic nerve was exposed but not crushed, was also evaluated. Functional recovery was then assessed by calculating the sciatic functional index (SFI) on days 0,1,7,14 and 21 in all groups, and registering the day of motor and walking onset. In comparison with control group, celecoxib treatment (experimental group) had significant beneficial effects on SFI, with a significantly better score on day 7. Anti-inflammatory drug celecoxib should be considered in the treatment of peripheral nerve injuries, but further studies are needed to explain the mechanism of its neuroprotective effects.
PMCID: PMC2607269  PMID: 19036161
5.  Electro-acupuncture promotes survival, differentiation of the bone marrow mesenchymal stem cells as well as functional recovery in the spinal cord-transected rats 
BMC Neuroscience  2009;10:35.
Bone marrow mesenchymal stem cells (MSCs) are one of the potential tools for treatment of the spinal cord injury; however, the survival and differentiation of MSCs in an injured spinal cord still need to be improved. In the present study, we investigated whether Governor Vessel electro-acupuncture (EA) could efficiently promote bone marrow mesenchymal stem cells (MSCs) survival and differentiation, axonal regeneration and finally, functional recovery in the transected spinal cord.
The spinal cords of adult Sprague-Dawley (SD) rats were completely transected at T10, five experimental groups were performed: 1. sham operated control (Sham-control); 2. operated control (Op-control); 3. electro-acupuncture treatment (EA); 4. MSCs transplantation (MSCs); and 5. MSCs transplantation combined with electro-acupuncture (MSCs+EA). After 2-8 weeks of MSCs transplantation plus EA treatment, we found that the neurotrophin-3 (NT-3), cAMP level, the differentiation of MSCs, the 5-HT positive and CGRP positive nerve fibers in the lesion site and nearby tissue of injured spinal cord were significantly increased in the MSCs+EA group as compared to the group of the MSCs transplantation or the EA treated alone. Furthermore, behavioral test and spinal cord evoked potentials detection demonstrated a significantly functional recovery in the MSCs +EA group.
These results suggest that EA treatment may promote grafted MSCs survival and differentiation; MSCs transplantation combined with EA treatment could promote axonal regeneration and partial locomotor functional recovery in the transected spinal cord in rats and indicate a promising avenue of treatment of spinal cord injury.
PMCID: PMC2679038  PMID: 19374777
6.  Reinnervation of the Tibialis Anterior Following Sciatic Nerve Crush Injury: A Confocal Microscopic Study in Transgenic Mice 
Experimental neurology  2007;207(1):64-74.
Transgenic mice whose axons and Schwann cells express fluorescent chromophores enable new imaging techniques and augment concepts in developmental neurobiology. The utility of these tools in the study of traumatic nerve injury depends on employing nerve models that are amenable to microsurgical manipulation and gauging functional recovery. Motor recovery from sciatic nerve crush injury is studied here by evaluating motor endplates of the tibialis anterior muscle, which is innervated by the deep peroneal branch of the sciatic nerve. Following sciatic nerve crush, the deep surface of the tibialis anterior muscle is examined using whole mount confocal microscopy, and reinnervation is characterized by imaging fluorescent axons or Schwann cells (SCs). One week following sciatic crush injury, 100% of motor endplates are denervated with partial reinnervation at two weeks, hyperinnervation at three and four weeks, and restoration of a 1:1 axon to motor endplate relationship six weeks after injury. Walking track analysis reveals progressive recovery of sciatic nerve function by six weeks. SCs reveal reduced S100 expression within two weeks of denervation, correlating with regression to a more immature phenotype. Reinnervation of SCs restores S100 expression and a fully differentiated phenotype. Following denervation, there is altered morphology of circumscribed terminal Schwann cells demonstrating extensive process formation between adjacent motor endplates. The thin, uniformly innervated tibialis anterior muscle is well suited for studying motor reinnervation following sciatic nerve injury. Confocal microscopy may be performed coincident with other techniques of assessing nerve regeneration and functional recovery.
PMCID: PMC2000860  PMID: 17628540
transgenic mice; chromophore; sciatic nerve crush; motor endplate
7.  Misdirection of regenerating motor axons after nerve injury and repair in the rat sciatic nerve model 
Experimental neurology  2008;211(2):339-350.
Misdirection of regenerating axons is one of the factors that can explain the poor results often found after nerve injury and repair. In this study, we quantified the degree of misdirection and the effect on recovery of function after different types of nerve injury and repair in the rat sciatic nerve model; crush injury, direct coaptation, and autograft repair. Sequential tracing with retrograde labeling of the peroneal nerve before and 8 weeks after nerve injury and repair was performed to quantify the accuracy of motor axon regeneration. Digital video analysis of ankle motion was used to investigate the recovery of function. In addition, serial compound action potential recordings and nerve and muscle morphometry were performed. In our study, accuracy of motor axon regeneration was found to be limited; only 71% (±4.9%) of the peroneal motoneurons were correctly directed 2 months after sciatic crush injury, 42% (±4.2%) after direct coaptation, and 25% (±6.6%) after autograft repair. Recovery of ankle motion was incomplete after all types of nerve injury and repair and demonstrated a disturbed balance of ankle plantar and dorsiflexion. The number of motoneurons from which axons had regenerated was not significantly different from normal. The number of myelinated axons was significantly increased distal to the site of injury. Misdirection of regenerating motor axons is a major factor in the poor recovery of nerves that innervate different muscles. The results of this study can be used as basis for developing new nerve repair techniques that may improve the accuracy of regeneration.
PMCID: PMC2967197  PMID: 18448099
Aberrant reinnervation; Accuracy of regeneration; Ankle motion analysis; Double labeling; Sequential retrograde tracing
8.  Retrograde tracing and toe spreading after experimental autologous nerve transplantation and crush injury of the sciatic nerve: a descriptive methodological study 
Evaluation of functional and structural recovery after peripheral nerve injury is crucial to determine the therapeutic effect of a nerve repair strategy. In the present study, we examined the relationship between the structural evaluation of regeneration by means of retrograde tracing and the functional analysis of toe spreading. Two standardized rat sciatic nerve injury models were used to address this relationship. As such, animals received either a 2 cm sciatic nerve defect (neurotmesis) followed by autologous nerve transplantation (ANT animals) or a crush injury with spontaneous recovery (axonotmesis; CI animals). Functional recovery of toe spreading was observed over an observation period of 84 days. In contrast to CI animals, ANT animals did not reach pre-surgical levels of toe spreading. After the observation period, the lipophilic dye DiI was applied to label sensory and motor neurons in dorsal root ganglia (DRG; sensory neurons) and spinal cord (motor neurons), respectively. No statistical difference in motor or sensory neuron counts could be detected between ANT and CI animals.
In the present study we could indicate that there was no direct relationship between functional recovery (toe spreading) measured by SSI and the number of labelled (motor and sensory) neurons evaluated by retrograde tracing. The present findings demonstrate that a multimodal approach with a variety of independent evaluation tools is essential to understand and estimate the therapeutic benefit of a nerve repair strategy.
PMCID: PMC3473253  PMID: 22546145
Peripheral nerve injury; Repair strategy; Peripheral nerve regeneration; Neurotmesis; SSI; Sciatic nerve injury; Rat model
9.  Axonally derived Neuregulin-1 is required for remyelination and regeneration following nerve injury in adulthood 
Neuregulin-1 (NRG1) plays a crucial role in axoglial signaling during the development of the peripheral nervous system, however its importance in adulthood following peripheral nerve injury remains unclear. We utilised Single-neuron Labelling with Inducible Cre-mediated Knockout (SLICK) animals, which enabled visualisation of a subset of adult myelinated sensory and motoneurons neurons in which Nrg1 was inducibly mutated by tamoxifen treatment. In uninjured mice, NRG1 deficient axons and the associated myelin sheath were normal and the neuromuscular junction demonstrated normal apposition of pre- and postsynaptic components. Following sciatic nerve crush, NRG1 ablation resulted in severe defects in remyelination: axons were either hypomyelinated or had no myelin sheath. NRG1 deficient axons were also found to regenerate at a slower rate. Following nerve injury the neuromuscular junction was reinnervated, however excess terminal sprouting was observed. Juxtacrine Neuregulin-1 signaling is therefore dispensable for maintenance of the myelin sheath in adult animals but has a key role in reparative processes following nerve injury.
PMCID: PMC3059576  PMID: 21368034
Neuregulin-1; Schwann cell; myelin; neuromuscular junction; regeneration
10.  Decreased MHC I expression in IFN gamma mutant mice alters synaptic elimination in the spinal cord after peripheral injury 
The histocompatibility complex (MHC) class I expression in the central nervous system (CNS) regulates synaptic plasticity events during development and adult life. Its upregulation may be associated with events such as axotomy, cytokine exposition and changes in neuron electrical activity. Since IFNγ is a potent inducer of the MHC I expression, the present work investigated the importance of this pro-inflammatory cytokine in the synaptic elimination process in the spinal cord, as well as the motor recovery of IFN−/−, following peripheral injury.
The lumbar spinal cords of C57BL/6J (wild type) and IFNγ−/− (mutant) mice, subjected to unilateral sciatic nerve transection, were removed and processed for immunohistochemistry and real time RT-PCR, while the sciatic nerves from animals subjected to unilateral crush, were submitted to immunohistochemistry and electron microscopy for counting of the axons. Gait recovery was monitored using the Cat Walk system. Newborn mice astrocyte primary cultures were established in order to study the astrocytic respose in the absence of the IFNγ expression.
IFNγ−/− mutant mice showed a decreased expression of MHC I and β2-microglobulin mRNA coupled with reduced synaptophysin immunolabelling in the lesioned spinal cord segment. Following unilateral nerve transection, the Iba-1 (ionized calcium binding adaptor molecule 1) and glial fibrillary acid protein (GFAP) reactivities increased equally in both strains. In vitro, the astrocytes demonstrated similar GFAP levels, but the proliferation rate was higher in the wild type mice. In the crushed nerves (distal stump), neurofilaments and p75NTR immunolabeling were upregulated in the mutant mice as compared to the wild type and an improvement in locomotor recovery was observed.
The present results show that a lack of IFNγ affects the MHC I expression and the synaptic elimination process in the spinal cord. Such changes, however, do not delay peripheral nerve regeneration after nerve injury.
PMCID: PMC3409034  PMID: 22564895
11.  Long-Term Effects of Axotomy on β-Tubulin and NF Gene Expression in Rat DRG Neurons 
To compare the long-term recovery of gene expression in dorsal root ganglion (DRG) neurons under conditions of regeneration vs. non-regeneration, Northern blotting and in situ hybridization were used to assess steady-state neurofilament (NF) and beta tubulin mRNA levels 12 weeks following axonal injury. Adult male rats sustained either a crush lesion of the mid-sciatic nerve (regeneration occurs), or a cut lesion of the sciatic nerve combined with ligation of the proximal nerve stump and removal of a large segment of the distal nerve (regeneration does not occur). In the latter case, neuroma formation physically prevented axonal regeneration. Results of Northern blotting of total RNA obtained from the DRG indicated that NF-L and NF-Μ mRNA levels had largely returned to control levels at 12 weeks following crush axotomy but were still substantially depressed following cut/ligation injury of the sciatic nerve at that time. in situ hybridization studies indicated that both crush and cut/ligation axotomy resulted in significantly lower NF-L mRNA levels in large-sized (>1000 μm2) DRG neurons at 12 weeks post-axotomy. Discrepancies in the conclusions from Northern blotting and in situ hybridization experiments were also noted in the case of tubulin mRNA changes at long intervals after axotomy. in situ hybridization data derived from the large-sized DRG neurons using a coding region β-tubulin cDNA (which recognizes both βII and βIII mRNAs) showed complete recovery of β-tubulin mRNA levels in surviving, large-sized DRG neurons after crush axotomy, but significantly elevated tubulin mRNA levels in surviving large DRG cells at 12 weeks after cut/ligation axotomy. In contrast, Northern blotting results indicated that βII-tubulin mRNA levels in the crush axotomy condition remained elevated relative to control while they were substantially lower than control in cut/ligation axotomy samples. Results from analysis of βIII-tubulin mRNA changes were not conclusive. The lack of complete correspondence in the results from the two different methods of analysis of mRNA changes (blotting vs. in situ) is likely to be due to selective loss of large-sized DRG neurons in the long-standing cut/ligation injury condition. This would influence results from blotting data, where RNA is derived from the DRG as a whole, more so than in situ hybridization experiments which specifically focus on the surviving largesized neurons. Overall, data from these experiments indicate that altered patterns of gene expression remain in the DRG for long intervals after axonal injury, whether or not axonal regeneration has been successful. However, recovery of “normal8221; patterns of cytoskeletal gene expression in the DRG is considerably more complete after crush injury than after cut/ligation injury.
PMCID: PMC2565286  PMID: 7703290
12.  Preliminary Investigation on Use of High-Resolution Optical Coherence Tomography to Monitor Injury and Repair in the Rat Sciatic Nerve 
Lasers in surgery and medicine  2010;42(4):306-312.
Background and Objective
Optical coherence tomography (OCT) has been used in limited settings to study peripheral nerve injury. The purpose of the study is to determine whether high-resolution OCT can be used to monitor nerve injury and regeneration in the rat sciatic nerve following crush injury, ligation, and transection with microsurgical repair.
Study Design/Materials and Methods
Forty-five rats were segregated into three groups. The right sciatic nerve was suture ligated (n = 15), cut then microsurgically repaired (n = 15), or crushed (n = 15). The left sciatic nerve served as the control; only surgical exposure and skin closure were performed. Each group was further divided into three subgroups where they were assigned survival durations of 4, 15, or 24 weeks. Following euthanasia, nerves were harvested, fixed in formalin, and imaged at the injury site, as well as proximal and distal ends. The OCT system resolution was approximately 7 μm in tissue with a 1,060 nm central wavelength.
Control (uninjured) nerve tissue showed homogenous signal distribution to a relatively uniform depth; in contrast, damaged nerves showed irregular signal distribution and intensity. Changes in signal distribution were most significant at the injury site and distal regions. Increases in signal irregularity were evident during longer recovery times. Histological analysis determined that OCT imaging was limited to the surrounding perineurium and scar tissue.
OCT has the potential to be a valuable tool for monitoring nerve injury and repair, and the changes that accompany wound healing, providing clinicians with a non-invasive tool to treat nerve injuries.
PMCID: PMC2898724  PMID: 20432279
nerve injury; peripheral nerve; optical coherence tomography and nerve
13.  Beneficial effects of treadmill training in experimental diabetic nerve regeneration 
Clinics  2010;65(12):1329-1337.
We investigated the effects of treadmill training (10 weeks) on hindlimb motor function and nerve morphometric parameters in diabetic rats submitted to sciatic nerve crush.
Wistar rats (n = 64) were divided into the following groups: non-diabetic; trained non-diabetic; non-diabetic with sciatic nerve crush; trained non-diabetic with sciatic nerve crush; diabetic; trained diabetic; diabetic with sciatic nerve crush or trained diabetic with sciatic nerve crush. Diabetes was induced by streptozotocin injection (50 mg/kg, iv). Hindlimb motor function was evaluated weekly by assessing sciatic functional indices, and the proximal and distal portions of the sciatic nerve were used for morphometric analysis.
At 13 weeks post-injury, the distal nerve portion of all injured groups and the proximal nerve portion of the diabetic with sciatic nerve crush group presented altered morphometric parameters such as decreased myelinated fiber diameter (∼7.4±0.3µm vs ∼4.8±0.2µm), axonal diameter (∼5±0.2µm vs ∼3.5±0.1µm) and myelin sheath thickness (∼1.2±0.07µm vs ∼0.65±0.07µm) and an increase in the percentage of area occupied by endoneurium (∼28±3% vs ∼60±3%). In addition, in the non-diabetic with sciatic nerve crush group the proximal nerve portion showed a decreased myelinated fiber diameter (7.4±0.3µm vs 5.8±0.3µm) and myelin sheath thickness (1.29±0.08µm vs 0.92±0.08µm). The non-diabetic with sciatic nerve crush, trained non-diabetic with sciatic nerve crush, diabetic with sciatic nerve crush and trained diabetic with sciatic nerve crush groups showed normal sciatic functional index from the 4th, 4th, 9th and 7th week post-injury, respectively. Morphometric alterations in the proximal nerve portion of the diabetic with sciatic nerve crush and non-diabetic with sciatic nerve crush groups were either prevented or reverted to values similar to the non-diabetic group by treadmill training.
Diabetic condition promoted delay in sciatic nerve regeneration. Treadmill training is able to accelerate hindlimb motor function recovery in diabetic injured rats and prevent or revert morphometric alterations in proximal nerve portions in non-diabetic and diabetic injured rats.
PMCID: PMC3020345  PMID: 21340223
Diabetes; Sciatic nerve crush; Motor function; Nerve morphometry; Treadmill training
14.  Persistent restoration of sensory function by immediate or delayed systemic artemin after dorsal root injury 
Nature neuroscience  2008;11(4):488-496.
Dorsal root injury results in substantial and often irreversible loss of sensory functions as a result of the limited regenerative capacity of sensory axons and the inhibitory barriers that prevent both axonal entry into and regeneration in the spinal cord. Here, we describe previously unknown effects of the growth factor artemin after crush injury of the dorsal spinal nerve roots in rats. Artemin not only promoted re-entry of multiple classes of sensory fibers into the spinal cord and re-establishment of synaptic function and simple behavior, but it also, surprisingly, promoted the recovery of complex behavior. These effects occurred after a 2-week schedule of intermittent, systemic administration of artemin and persisted for at least 6 months following treatment, suggesting a substantial translational advantage. Systemic artemin administration produced essentially complete and persistent restoration of nociceptive and sensorimotor functions, and could represent a promising therapy that may effectively promote sensory neuronal regeneration and functional recovery after injury.
PMCID: PMC3417340  PMID: 18344995
15.  Matching of motor-sensory modality in the rodent femoral nerve model shows no enhanced effect on peripheral nerve regeneration 
Experimental neurology  2010;223(2):496-504.
The treatment of peripheral nerve injuries with nerve gaps largely consists of autologous nerve grafting utilizing sensory nerve donors. Underlying this clinical practice is the assumption that sensory autografts provide a suitable substrate for motoneuron regeneration, thereby facilitating motor endplate reinnervation and functional recovery. This study examined the role of nerve graft modality on axonal regeneration, comparing motor nerve regeneration through motor, sensory, and mixed nerve isografts in the Lewis rat. A total of 100 rats underwent grafting of the motor or sensory branch of the femoral nerve with histomorphometric analysis performed after 5, 6, or 7 weeks. Analysis demonstrated similar nerve regeneration in motor, sensory, and mixed nerve grafts at all three time points. These data indicate that matching of motor-sensory modality in the rat femoral nerve does not confer improved axonal regeneration through nerve isografts.
PMCID: PMC2865885  PMID: 20122927
Femoral nerve; preferential motor regeneration; nerve architecture; motor graft; sensory graft; modality-specific regeneration
16.  Deletion of Nrf2 impairs functional recovery, reduces clearance of myelin debris and decreases axonal remyelination after peripheral nerve injury 
Neurobiology of disease  2013;54:329-338.
Oxidative stress is generated in several peripheral nerve injury models. In response to oxidative stress, the transcription factor Nrf2 is activated to induce expression of antioxidant responsive element (ARE) genes. The role of Nrf2 in peripheral nerve injury has not been studied to date. In this study, we used a sciatic nerve crush model to examine how deletion of Nrf2 affects peripheral nerve degeneration and regeneration. Our study demonstrated that functional recovery in the Nrf2-/- mice were impaired compared to the wild type mice after sciatic nerve crush. Larger myelin debris were present in the distal nerve stump of the Nrf2-/- mice than in the wild type mice. The presence of larger myelin debris in the Nrf2-/- mice coincides with less macrophages accumulation in the distal nerve stump. Less accumulation of macrophages may have contributed to slower clearance of myelin and thus resulted in the presence of larger myelin debris. Meanwhile, axonal regeneration is comparatively lower in the Nrf2-/- mice than in the wild type mice. Even after 3 months post the injury, more thinly myelinated axon fibers were present in the Nrf2-/- mice than in the wild type mice. Taken collectively, these data support the concept of therapeutic intervention with Nrf2 activators following nerve injury.
PMCID: PMC3628945  PMID: 23328769
Nrf2; sciatic nerve crush; myelin clearance; axonal regeneration; remyelination
17.  Basement Membrane and Repair of Injury to Peripheral Nerve: Defining a Potential Role for Macrophages, Matrix Metalloproteinases, and Tissue Inhibitor of Metalloproteinases-1 
The Journal of Experimental Medicine  1996;184(6):2311-2326.
Injury to a peripheral nerve is followed by a remodeling process consisting of axonal degeneration and regeneration. It is not known how Schwann cell–derived basement membrane is preserved after injury or what role matrix metalloproteinases (MMPs) and their inhibitors play in axonal degeneration and regeneration. We showed that the MMPs gelatinase B (MMP-9), stromelysin-1 (MMP-3), and the tissue inhibitor of MMPs (TIMP)-1 were induced in crush and distal segments of mouse sciatic nerve after injury. TIMP-1 inhibitor activity was present in excess of proteinase activity in extracts of injured nerve. TIMP-1 protected basement membrane type IV collagen from degradation by exogenous gelatinase B in cryostat sections of nerve in vitro. In vivo, during the early phase (1 d after crush) and later phase (4 d after crush) after injury, induction of TNF-α and TGF-β1 mRNAs, known modulators of TIMP-1 expression, were paralleled by an upregulation of TIMP-1 and gelatinase B mRNAs. At 4 days after injury, TIMP-1, gelatinase B, and TNF-α mRNAs were localized to infiltrating macrophages and Schwann cells in the regions of nerve infiltrated by elicited macrophages. TIMP-1 and cytokine mRNA expression was upregulated in undamaged nerve explants incubated with medium conditioned by macrophages or containing the cytokines TGF-β1, TNF-α, and IL-1α. These results show that TIMP-1 may protect basement membrane from uncontrolled degradation after injury and that cytokines produced by macrophages may participate in the regulation of TIMP-1 levels during nerve repair.
PMCID: PMC2196375  PMID: 8976186
18.  Effect of Zofenopril on regeneration of sciatic nerve crush injury in a rat model 
Zofenopril is an antioxidant agent which has been shown to have beneficial effects in hypertension and heart failure. The aim of this study was to test the effects of Zofenopril on nerve regeneration and scarring in a rat model of peripheral nerve crush injury.
Twenty-one adult Sprague-Dawley rats underwent a surgical procedure involving right sciatic nerve crush injury. 15 mg/kg Zofenopril was administered orally to seven rats in group Z for seven days. Seven rats in group S received saline orally for seven days. Seven rats in the control group C received no drug after crush injury. Fourteenth and 42nd days after injury, functional and electromyography assessments of nerves were performed. Functional recovery was analyzed using a walking track assessment, and quantified using the sciatic functional index (SFI). After these evaluations, all rats were sacrificed and microscopic evaluations were performed.
The Sciatic functional Index (SFI) in group Z on 14th day is different significantly from group S and group C (p = 0.037). But on 42nd day there was no difference between groups (p = 0.278). The statistical analyses of electromyelographic (EMG) studies showed that the latency in group Z is significantly different from group S (p = 0.006) and group C (p = 0.045). But on 42nd day there was no difference between groups like SFI (p = 0.147). The amplitude was evaluated better in group Z than others (p < 0.05). In microscopic evaluation, we observed the highest number of nerve regeneration in the group Z and the lowest in the group C. But it was not significant statistically.
Our results demonstrate that Zofenopril promotes the regeneration of peripheral nerve injuries in rat models.
PMCID: PMC2700796  PMID: 19508704
19.  In vivo evaluation of demyelination and remyelination in a nerve crush injury model 
Biomedical Optics Express  2011;2(9):2698-2708.
Nerves of the peripheral nervous system have, to some extent, the ability to regenerate after injury, particularly in instances of crush or contusion injuries. After a controlled crush injury of the rat sciatic nerve, demyelination and remyelination are followed with functional assessments and imaged both ex vivo and in vivo over the course of 4 weeks with video-rate coherent anti-Stokes Raman scattering (CARS) microscopy. A new procedure compatible with live animal imaging is developed for performing histomorphometry of myelinated axons. This allows quantification of demyelination proximal and remyelination distal to the crush site ex vivo and in vivo respectively.
PMCID: PMC3184878  PMID: 22091449
(170.3880) Medical and biological imaging; (190.4180) Multiphoton processes; (180.4315) Nonlinear microscopy; (180.5655) Raman microscopy
20.  The Microenvironment-Specific Transformation of Adult Stem Cells Models Malignant Triton Tumors 
PLoS ONE  2013;8(12):e82173.
Here, we demonstrated the differentiation potential of murine muscle-derived stem/progenitor cells (MDSPCs) toward myogenic, neuronal, and glial lineages. MDSPCs, following transplantation into a critical-sized sciatic nerve defect in mice, showed full regeneration with complete functional recovery of the injured peripheral nerve at 6 weeks post-implantation. However, several weeks after regeneration of the sciatic nerve, neoplastic growths were observed. The resulting tumors were malignant peripheral nerve sheath tumors (MPNSTs) with rhabdomyoblastic differentiation, expressing myogenic, neurogenic, and glial markers, common markers of human malignant triton tumors (MTTs). No signs of tumorigenesis were observed 17 weeks post-implantation of MDSPCs into the gastrocnemius muscles of dystrophic/mdx mice, or 1 year following subcutaneous or intravenous injection. While MDSPCs were not oncogenic in nature, the neoplasias were composed almost entirely of donor cells. Furthermore, cells isolated from the tumors were serially transplantable, generating tumors when reimplanted into mice. However, this transformation could be abrogated by differentiation of the cells toward the neurogenic lineage prior to implantation. These results establish that MDSPCs participated in the regeneration of the injured peripheral nerve but transformed in a microenvironment- and time-dependent manner, when they likely received concomitant neurogenic and myogenic differentiation signals. This microenvironment-specific transformation provides a useful mouse model for human MTTs and potentially some insight into the origins of this disease.
PMCID: PMC3857244  PMID: 24349213
21.  Antiallodynic Effects of Acupuncture in Neuropathic Rats 
Yonsei Medical Journal  2006;47(3):359-366.
Peripheral nerve injury often results in abnormal neuropathic pain such as allodynia or hyperalgesia. Acupuncture, a traditional Oriental medicine, has been used to relieve pain and related symptoms. However, the efficiency of acupuncture in relieving neuropathic pain is not clear. The aim of this study was to investigate the anti-allodynic effects of acupuncture through behavioral and electrophysiological examinations. Male Sprague-Dawley rats were subjected to neuropathic surgery consisting of a tight ligation and transection of the left tibial and sural nerves, under pentobarbital anesthesia. The acupuncture experiment consisted of four different groups, one treated at each of three different acupoints (Zusanli (ST36), Yinlingquan (SP9), and a sham-acupoint) and a control group. Behavioral tests for mechanical allodynia and cold allodynia were performed for up to two weeks postoperatively. Extracellular electrophysiological recordings were made from the dorsal roots using platinum wire electrodes. Mechanical and cold allodynia were significantly reduced after acupuncture treatment at the Zusanli and Yinlingquan acupoints, respectively. Electrophysiological neural responses to von Frey and acetone tests were also reduced after acupuncture at the same two acupoints. These results suggest that acupuncture may be beneficial in relieving neuropathic pain.
PMCID: PMC2688155  PMID: 16807985
Neuropathic pain; acupuncture; acupoint; allodynia; electrophysiology
22.  Comparison and Evaluation of Current Animal Models for Perineural Scar Formation in Rat 
Objective (s): Scar formation in injured peripheral nerve bed causes several consequences which impede the process of nerve regeneration. Several animal models are used for scar induction in preclinical studies which target prevention and/or suppression of perineural scar. This study evaluates the translational capacity of four of physical injury models to induce scar formation around the sciatic nerve of rat: laceration, crush, mince and burn.
Materials and Methods: Functional (Toe out angle), macroscopic, and microscopic evaluations were performed weekly for four weeks and correlation of findings were analyzed.
Result: While macroscopic and microscopic findings suggested a well-developed and adhesive fibrosis surrounding the sciatic nerve, functional assessment did not reveal any significant difference between control and experimental groups (P>0.05).
Conclusion: Our study suggests that none of the applied animal models reproduce all essential features of clinical perineural scar formation. Therefore, more studies are needed to develop optimal animal models for translating preclinical investigations.
PMCID: PMC3758062  PMID: 23997921
Scar; Sciatic nerve; Translational research
23.  Mechanisms of Enhancement of Neurite Regeneration In Vitro Following a Conditioning Sciatic Nerve Lesion 
To examine the mechanisms responsible for the more rapid nerve regeneration observed after a previous (conditioning) nerve injury, adult rats were subjected to a midthigh sciatic nerve transection by using one of three protocols designed to facilitate or restrict nerve regeneration: 1) ligation, in which transected axons were prevented from regenerating; 2) cut, in which transected axons were permitted to extend into peripheral target tissue but were separated from the denervated peripheral nerve stump; and 3) crush, in which axons could regenerate normally through the denervated distal nerve tract. The affected dorsal root ganglia (DRG) were subsequently removed, dissociated, and cultured for up to 3 days, and the timing of neurite initiation, rate of outgrowth, and arborization pattern of previously injured neurons were compared with control DRG. Our results indicate that conditioning lesions have at least four distinct and differentially regulated effects on neuronal morphogenesis: 1) conditioning lesions promote earlier neurite initiation, 2) prior nerve injury decreases the ability of neurons to extend long neurites following a second axotomy, 3) exposure to the environment of a denervated peripheral nerve stimulates greater initial rates of neurite outgrowth, and 4) conditioning lesions reduces initial neuritic branching frequency, resulting in straighter neurites whose growth cones extend further distances from their cell bodies. The primary effect of all conditioning lesions on cultured DRG neurons appeared to be to advance the timing of morphogenesis, resulting in conditioning-lesioned neurons that exhibited characteristics consistent with control neurons that had been cultured for an additional day or more. A secondary effect of conditioning lesions on neurite outgrowth rates was dependent on the local environment of the axons prior to culturing.
PMCID: PMC2605358  PMID: 9527536
neurite outgrowth; neurite initiation; nerve regeneration; conditioning lesion; neurite arborization
24.  Brain-Derived Neurotrophic Factor from Bone Marrow-Derived Cells Promotes Post-Injury Repair of Peripheral Nerve 
PLoS ONE  2012;7(9):e44592.
Brain-derived neurotrophic factor (BDNF) stimulates peripheral nerve regeneration. However, the origin of BNDF and its precise effect on nerve repair have not been clarified. In this study, we examined the role of BDNF from bone marrow-derived cells (BMDCs) in post-injury nerve repair. Control and heterozygote BDNF knockout mice (BDNF+/−) received a left sciatic nerve crush using a cerebral blood clip. Especially, for the evaluation of BDNF from BMDCs, studies with bone marrow transplantation (BMT) were performed before the injury. We evaluated nerve function using a rotarod test, sciatic function index (SFI), and motor nerve conduction velocity (MNCV) simultaneously with histological nerve analyses by immunohistochemistry before and after the nerve injury until 8 weeks. BDNF production was examined by immunohistochemistry and mRNA analyses. After the nerve crush, the controls showed severe nerve dysfunction evaluated at 1 week. However, nerve function was gradually restored and reached normal levels by 8 weeks. By immunohistochemistry, BDNF expression was very faint before injury, but was dramatically increased after injury at 1 week in the distal segment from the crush site. BDNF expression was mainly co-localized with CD45 in BMDCs, which was further confirmed by the appearance of GFP-positive cells in the BMT study. Variant analysis of BDNF mRNA also confirmed this finding. BDNF+/− mice showed a loss of function with delayed histological recovery and BDNF+/+→BDNF+/− BMT mice showed complete recovery both functionally and histologically. These results suggested that the attenuated recovery of the BDNF+/− mice was rescued by the transplantation of BMCs and that BDNF from BMDCs has an essential role in nerve repair.
PMCID: PMC3446933  PMID: 23028564
25.  A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. 
Journal of Clinical Investigation  1989;83(3):1015-1031.
Recent work has demonstrated that apo E secretion and accumulation increase in the regenerating peripheral nerve. The fact that apoE, in conjunction with apoA-I and LDL receptors, participates in a well-established lipid transfer system raised the possibility that apoE is also involved in lipid transport in the injured nerve. In the present study of the crushed rat sciatic nerve, a combination of techniques was used to trace the cellular associations of apoE, apoA-I, and the LDL receptor during nerve repair and to determine the distribution of lipid at each stage. After a crush injury, as axons died and Schwann cells reabsorbed myelin, resident and monocyte-derived macrophages produced large quantities of apoE distal to the injury site. As axons regenerated in the first week, their tips contained a high concentration of LDL receptors. After axon regeneration, apoE and apoA-I began to accumulate distal to the injury site and macrophages became increasingly cholesterol-loaded. As remyelination began in the second and third weeks after injury, Schwann cells exhausted their cholesterol stores, then displayed increased LDL receptors. Depletion of macrophage cholesterol stores followed over the next several weeks. During this stage of regeneration, apoE and apoA-I were present in the extracellular matrix as components of cholesterol-rich lipoproteins. Our results demonstrate that the regenerating peripheral nerve possesses the components of a cholesterol transfer mechanism, and the sequence of events suggests that this mechanism supplies the cholesterol required for rapid membrane biogenesis during axon regeneration and remyelination.
PMCID: PMC303779  PMID: 2493483

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