scholarly journals Upslope treadmill exercise enhances motor axon regeneration but not functional recovery following peripheral nerve injury

2016 ◽  
Vol 116 (3) ◽  
pp. 1408-1417 ◽  
Author(s):  
Jill Cannoy ◽  
Sam Crowley ◽  
Allen Jarratt ◽  
Kelly LeFevere Werts ◽  
Krista Osborne ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Functional Recovery ◽  
Peripheral Nerve Injury ◽  
Axon Regeneration ◽  
Motor Axon ◽  
Emg Activity ◽  
Daily Exercise ◽  
Muscle Reinnervation

Following peripheral nerve injury, moderate daily exercise conducted on a level treadmill results in enhanced axon regeneration and modest improvements in functional recovery. If the exercise is conducted on an upwardly inclined treadmill, even more motor axons regenerate successfully and reinnervate muscle targets. Whether this increased motor axon regeneration also results in greater improvement in functional recovery from sciatic nerve injury was studied. Axon regeneration and muscle reinnervation were studied in Lewis rats over an 11 wk postinjury period using stimulus evoked electromyographic (EMG) responses in the soleus muscle of awake animals. Motor axon regeneration and muscle reinnervation were enhanced in slope-trained rats. Direct muscle (M) responses reappeared faster in slope-trained animals than in other groups and ultimately were larger than untreated animals. The amplitude of monosynaptic H reflexes recorded from slope-trained rats remained significantly smaller than all other groups of animals for the duration of the study. The restoration of the amplitude and pattern of locomotor EMG activity in soleus and tibialis anterior and of hindblimb kinematics was studied during treadmill walking on different slopes. Slope-trained rats did not recover the ability to modulate the intensity of locomotor EMG activity with slope. Patterned EMG activity in flexor and extensor muscles was not noted in slope-trained rats. Neither hindblimb length nor limb orientation during level, upslope, or downslope walking was restored in slope-trained rats. Slope training enhanced motor axon regeneration but did not improve functional recovery following sciatic nerve transection and repair.

scholarly journals The long noncoding RNA Arrl1 inhibits neurite outgrowth by functioning as a competing endogenous RNA during neuronal regeneration in rats

2020 ◽  
Vol 295 (25) ◽  
pp. 8374-8386 ◽  
Author(s):  
Dong Wang ◽  
Yanping Chen ◽  
Mingwen Liu ◽  
Qianqian Cao ◽  
Qihui Wang ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Neurite Outgrowth ◽  
Nerve Injury ◽  
Functional Recovery ◽  
Peripheral Nerve Injury ◽  
Axon Regeneration ◽  
Neuronal Regeneration ◽  
Competing Endogenous Rna ◽  
Drg Neurons

The intrinsic regeneration ability of neurons is a pivotal factor in the repair of peripheral nerve injury. Therefore, identifying the key modulators of nerve regeneration may help improve axon regeneration and functional recovery after injury. Unlike for classical transcription factors and regeneration-associated genes, the function of long noncoding RNAs (lncRNAs) in the regulation of neuronal regeneration remains mostly unknown. In this study, we used RNA-Seq–based transcriptome profiling to analyze the expression patterns of lncRNAs and mRNAs in rat dorsal root ganglion (DRG) following sciatic nerve injury. Analyses using the lncRNA-mRNA co-expression network, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway databases indicated that the lncRNA Arrl1 decreases neurite outgrowth after neuronal injury. shRNA-mediated Arrl1 silencing increased axon regeneration both in vitro and in vivo and improved functional recovery of the sciatic nerve. Moreover, inhibiting an identified target gene of Arrl1, cyclin-dependent kinase inhibitor 2B (Cdkn2b), markedly promoted neurite outgrowth of DRG neurons. We also found that Arrl1 acts as a competing endogenous RNA that sponges a Cdkn2b repressor, microRNA-761 (miR-761), and thereby up-regulates Cdkn2b expression during neuron regeneration. We conclude that the lncRNA Arrl1 affects the intrinsic regeneration of DRG neurons by derepressing Cdkn2b expression. Our findings indicate a role for an lncRNA-microRNA-kinase pathway in the regulation of axon regeneration and functional recovery following peripheral nerve injury in rats.

scholarly journals Functional Recovery via Preregenerated Nerve Graft in Rat Sciatic Nerve Injury Model

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Umang Khandpur ◽  
Ying Yan ◽  
Wilson Zachary Ray ◽  
Matthew R MacEwan
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Functional Recovery ◽  
Peripheral Nerve Injury ◽  
Muscle Force ◽  
Nerve Graft ◽  
Tissue Loss ◽  
Limb Amputation ◽  
Percent Recovery

Abstract INTRODUCTION Patients who have experienced major tissue loss with peripheral nerve injury (eg, limb amputation) may be offered composite tissue allotransplantation (CTA). The return of sensory ability and cosmetic component of CTAs make them an attractive alternative to prosthetic devices. Unfortunately, robust reinnervation especially over great distances remains an issue for hand allotransplants. In this study, we introduce a preregenerated nerve graft to shorten the distance and therefore time to terminal tissue reinnervation, which could improve the utility of CTAs. METHODS A total of 18 rats weighing 250 to 300 gm each were randomized into 1 of 3 groups: baseline, fresh, or preregenerated. The baseline group underwent sham surgery to obtain baseline functional data. The fresh and preregenerated groups both underwent grafting of the sciatic nerve but the preregenerated group utilized 8-wk preregenerated grafts. At postperative week 8 from distal neurorrhaphy, both groups underwent terminal functional testing via EMG and evoked muscle force. RESULTS The preregenerated group had significantly greater mean EMG (P < .05) and maximum tetanic muscle force values (P < .05) than the fresh group. Mean percent recovery in EMG for the fresh group was 21.95% compared with 81.79% in the preregenerated group. Mean percent recovery in muscle force was 9.46% and 33.15%, respectively. CONCLUSION The results of this study provide a novel approach to enhance final functional recovery after peripheral nerve injury. The current practice of constructing a nerve stump may be improved by grafting a nerve segment at the time of injury and allowing it to preregenerate into local musculature so that if a CTA is later performed, an expedited and more robust reinnervation could be accomplished.

scholarly journals Bioinformatics analysis of long non-coding RNAs involved in nerve regeneration following sciatic nerve injury

2020 ◽  
Vol 16 ◽  
pp. 174480692097191
Author(s):  
Yuanyuan Jia ◽  
Ming Zhang ◽  
Pei Li ◽  
Wenbo Tang ◽  
Yao Liu ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Axon Regeneration ◽  
Sciatic Nerve Injury ◽  
Sciatic Nerve Crush ◽  
Non Coding Rnas

Little is known about the role of epigenetic modification in axon regeneration following peripheral nerve injury. The purpose of the present study was to investigate the role of long non-coding RNAs (lncRNAs) in the regulation of axon regeneration. We used bioinformatics to perform microarray analysis and screened total 476 lncRNAs and 129 microRNAs (miRNAs) of differentially expressed genes after sciatic nerve injury in mice. lncRNA-GM4208 and lncRNA-GM30085 were examined, and the changes in lncRNA expression in the L4–L6 dorsal root ganglia (DRG) following sciatic nerve crush injury were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression of lncRNAs in the DRG changed, indicating that they might be related to nerve regeneration in the DRG following peripheral nerve injury.

scholarly journals Time course of functional recovery during the first 3 mo after surgical transection and repair of nerves to the feline soleus and lateral gastrocnemius muscles

2018 ◽  
Vol 119 (3) ◽  
pp. 1166-1185 ◽  
Author(s):  
Robert J. Gregor ◽  
Huub Maas ◽  
Margarita A. Bulgakova ◽  
Alanna Oliver ◽  
Arthur W. English ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Nerve Injury ◽  
Functional Recovery ◽  
Peripheral Nerve Injury ◽  
Stretch Reflex ◽  
Medial Gastrocnemius ◽  
Emg Activity ◽  
Lateral Gastrocnemius ◽  
Injury And Repair ◽  
Central Drive

Locomotion outcomes after peripheral nerve injury and repair in cats have been described in the literature for the period immediately following the injury (muscle denervation period) and then again for an ensuing period of long-term recovery (at 3 mo and longer) resulting in muscle self-reinnervation. Little is known about the changes in muscle activity and walking mechanics during midrecovery, i.e., the early reinnervation period that takes place between 5 and 10 wk of recovery. Here, we investigated hindlimb mechanics and electromyogram (EMG) activity of ankle extensors in six cats during level and slope walking before and every 2 wk thereafter in a 14-wk period of recovery after the soleus (SO) and lateral gastrocnemius (LG) muscle nerves in one hindlimb were surgically transected and repaired. We found that the continued increase in SO and LG EMG magnitudes and corresponding changes in hindlimb mechanics coincided with the formation of neuromuscular synapses revealed in muscle biopsies. Throughout the recovery period, EMG magnitude of SO and LG during the stance phase and the duration of the stance-related activity were load dependent, similar to those in the intact synergistic medial gastrocnemius and plantaris. These results and the fact that EMG activity of ankle extensors and locomotor mechanics during level and upslope walking recovered 14 wk after nerve transection and repair suggest that loss of the stretch reflex in self-reinnervated muscles may be compensated by the recovered force-dependent feedback in self-reinnervated muscles, by increased central drive, and by increased gain in intermuscular motion-dependent pathways from intact ankle extensors. NEW & NOTEWORTHY This study provides new evidence that the timeline for functional recovery of gait after peripheral nerve injury and repair is consistent with the time required for neuromuscular junctions to form and muscles to reach preoperative tensions. Our findings suggest that a permanent loss of autogenic stretch reflex in self-reinnervated muscles may be compensated by recovered intermuscular force-dependent and oligosynaptic length-dependent feedback and central drive to regain adequate locomotor output capabilities during level and upslope walking.

scholarly journals Effects of treadmill training on functional recovery following peripheral nerve injury in rats

2013 ◽  
Vol 109 (11) ◽  
pp. 2645-2657 ◽  
Author(s):  
Tiffany Boeltz ◽  
Meredith Ireland ◽  
Kristin Mathis ◽  
Jennifer Nicolini ◽  
Karen Poplavski ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Injury ◽  
Functional Recovery ◽  
Tibialis Anterior ◽  
Axon Regeneration ◽  
Treadmill Training ◽  
Female Rats ◽  
Nerve Transection ◽  
Sciatic Nerve Transection ◽  
Daily Exercise

Exercise, in the form of moderate daily treadmill training following nerve transection and repair leads to enhanced axon regeneration, but its effect on functional recovery is less well known. Female rats were exercised by walking continuously, at a slow speed (10 m/min), for 1 h/day on a level treadmill, beginning 3 days after unilateral transection and surgical repair of the sciatic nerve, and conducted 5 days/wk for 2 wk. In Trained rats, both direct muscle responses to tibial nerve stimulation and H reflexes in soleus reappeared earlier and increased in amplitude more rapidly over time than in Untrained rats. The efficacy of the restored H reflex was greater in Trained rats than in Untrained controls. The reinnervated tibialis anterior and soleus were coactivated during treadmill locomotion in Untrained rats. In Trained animals, the pattern of activation of soleus, but not tibialis anterior, was not significantly different from that found in Intact rats. The overall length of the hindlimb during level and up- and downslope locomotion was conserved after nerve injury in both groups. This conservation was achieved by changes in limb orientation. Limb length was conserved effectively in all rats during downslope walking but only in Trained rats during level and upslope walking. Moderate daily exercise applied immediately after sciatic nerve transection is sufficient to promote axon regeneration, to restore muscle reflexes, and to improve the ability of rats to cope with different biomechanical demands of slope walking.

Changes in Crossed Spinal Reflexes After Peripheral Nerve Injury and Repair

2002 ◽  
Vol 87 (4) ◽  
pp. 1763-1771 ◽  
Author(s):  
Antoni Valero-Cabré ◽  
Xavier Navarro
Keyword(s):  
Sciatic Nerve ◽  
Action Potential ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Tibialis Anterior ◽  
Tibial Nerve ◽  
Spinal Reflexes ◽  
Injury And Repair

We investigated the changes induced in crossed extensor reflex responses after peripheral nerve injury and repair in the rat. Adults rats were submitted to non repaired sciatic nerve crush (CRH, n = 9), section repaired by either aligned epineurial suture (CS, n = 11) or silicone tube (SIL4, n = 13), and 8 mm resection repaired by tubulization (SIL8, n = 12). To assess reinnervation, the sciatic nerve was stimulated proximal to the injury site, and the evoked compound muscle action potential (M and H waves) from tibialis anterior and plantar muscles and nerve action potential (CNAP) from the tibial nerve and the 4th digital nerve were recorded at monthly intervals for 3 mo postoperation. Nociceptive reinnervation to the hindpaw was also assessed by plantar algesimetry. Crossed extensor reflexes were evoked by stimulation of the tibial nerve at the ankle and recorded from the contralateral tibialis anterior muscle. Reinnervation of the hindpaw increased progressively with time during the 3 mo after lesion. The degree of muscle and sensory target reinnervation was dependent on the severity of the injury and the nerve gap created. The crossed extensor reflex consisted of three bursts of activity (C1, C2, and C3) of gradually longer latency, lower amplitude, and higher threshold in control rats. During follow-up after sciatic nerve injury, all animals in the operated groups showed recovery of components C1 and C2 and of the reflex H wave, whereas component C3 was detected in a significantly lower proportion of animals in groups with tube repair. The maximal amplitude of components C1 and C2 recovered to values higher than preoperative values, reaching final levels between 150 and 245% at the end of the follow-up in groups CRH, CS, and SIL4. When reflex amplitude was normalized by the CNAP amplitude of the regenerated tibial nerve, components C1 (300–400%) and C2 (150–350%) showed highly increased responses, while C3 was similar to baseline levels. In conclusion, reflexes mediated by myelinated sensory afferents showed, after nerve injuries, a higher degree of facilitation than those mediated by unmyelinated fibers. These changes tended to decline toward baseline values with progressive reinnervation but still remained significant 3 mo after injury.

scholarly journals Bioluminescent Optogenetics: A Novel Experimental Therapy to Promote Axon Regeneration after Peripheral Nerve Injury

2021 ◽  
Vol 22 (13) ◽  
pp. 7217
Author(s):  
Arthur W. English ◽  
Ken Berglund ◽  
Dario Carrasco ◽  
Katharina Goebel ◽  
Robert E. Gross ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Viral Vectors ◽  
Axon Regeneration ◽  
Intraperitoneal Administration ◽  
Experimental Therapy ◽  
Promising Therapeutic Approach ◽  
Compound Muscle Action Potentials

Functional recovery after peripheral nerve injury (PNI) is poor, mainly due to the slow and incomplete regeneration of injured axons. Experimental therapies that increase the excitability of the injured axons have proven remarkably successful in promoting regeneration, but their clinical applicability has been limited. Bioluminescent optogenetics (BL-OG) uses luminopsins, fusion proteins of light-generating luciferase and light-sensing ion channels that could be used to increase neuronal excitability if exposed to a suitable substrate. Excitatory luminopsins were expressed in motoneurons of transgenic mice and in wildtype mice transduced with adeno-associated viral vectors. Intraperitoneal administration of coelenterazine (CTZ), a known luciferase substrate, generated intense bioluminescence in peripheral axons. This bioluminescence increased motoneuron excitability. A single administration of CTZ immediately after sciatic nerve transection and repair markedly enhanced motor axon regeneration. Compound muscle action potentials were 3–4 times larger than controls by 4 weeks after injury. The results observed with transgenic mice were comparable to those of mice in which the luminopsin was expressed using viral vectors. Significantly more motoneurons had successfully reinnervated muscle targets four weeks after nerve injury in BL-OG treated mice than in controls. Bioluminescent optogenetics is a promising therapeutic approach to enhancing axon regeneration after PNI.

scholarly journals SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury

2021 ◽  
Vol 17 ◽  
pp. 174480692110066
Author(s):  
Orest Tsymbalyuk ◽  
Volodymyr Gerzanich ◽  
Aaida Mumtaz ◽  
Sanketh Andhavarapu ◽  
Svetlana Ivanova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Thermal Sensitivity ◽  
Gradual Improvement ◽  
Pain Behaviors

Background Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL -6 ), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. Methods Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. Results Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. Conclusion SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

Comparing axon regeneration in male and female mice after peripheral nerve injury

2021 ◽  
Author(s):  
Eun‐Hae Jang ◽  
Yun‐Hee Bae ◽  
Eun Mo Yang ◽  
Yunho Gim ◽  
Hyun‐Jun Suh ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Axon Regeneration ◽  
Male And Female ◽  
Female Mice

Transplantation of Schwann cells in a collagen tube for the repair of large, segmental peripheral nerve defects in rats

2013 ◽  
Vol 119 (3) ◽  
pp. 720-732 ◽  
Author(s):  
Yerko A. Berrocal ◽  
Vania W. Almeida ◽  
Ranjan Gupta ◽  
Allan D. Levi
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Fluorescent Protein ◽  
Control Groups ◽  
Myelinated Axons ◽  
Segmental Nerve ◽  
Green Fluorescent

Object Segmental nerve defects pose a daunting clinical challenge, as peripheral nerve injury studies have established that there is a critical nerve gap length for which the distance cannot be successfully bridged with current techniques. Construction of a neural prosthesis filled with Schwann cells (SCs) could provide an alternative treatment to successfully repair these long segmental gaps in the peripheral nervous system. The object of this study was to evaluate the ability of autologous SCs to increase the length at which segmental nerve defects can be bridged using a collagen tube. Methods The authors studied the use of absorbable collagen conduits in combination with autologous SCs (200,000 cells/μl) to promote axonal growth across a critical size defect (13 mm) in the sciatic nerve of male Fischer rats. Control groups were treated with serum only–filled conduits of reversed sciatic nerve autografts. Animals were assessed for survival of the transplanted SCs as well as the quantity of myelinated axons in the proximal, middle, and distal portions of the channel. Results Schwann cell survival was confirmed at 4 and 16 weeks postsurgery by the presence of prelabeled green fluorescent protein–positive SCs within the regenerated cable. The addition of SCs to the nerve guide significantly enhanced the regeneration of myelinated axons from the nerve stump into the proximal (p < 0.001) and middle points (p < 0.01) of the tube at 4 weeks. The regeneration of myelinated axons at 16 weeks was significantly enhanced throughout the entire length of the nerve guide (p < 0.001) as compared with their number in a serum–only filled tube and was similar in number compared with the reversed autograft. Autotomy scores were significantly lower in the animals whose sciatic nerve was repaired with a collagen conduit either without (p < 0.01) or with SCs (p < 0.001) when compared with a reversed autograft. Conclusions The technique of adding SCs to a guidance channel significantly enhanced the gap distance that can be repaired after peripheral nerve injury with long segmental defects and holds promise in humans. Most importantly, this study represents some of the first essential steps in bringing autologous SC-based therapies to the domain of peripheral nerve injuries with long segmental defects.

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