204 Voluntary Exercise Modulates Macrophage Polarization Following Sciatic Nerve Injury and Improves Functional Recovery in Mice

Abstract INTRODUCTION Peripheral nerve injury is associated with trauma and is often amenable to surgery. Functional recovery remains a challenging clinical problem that often leads to significant morbidity. Therapies that augment surgical repair may be beneficial in functional outcomes. Macrophages are responsible for the breakdown of debris following injury as well as promotion of regenerative signals. Macrophage polarization is the process by which macrophages take on phenotypically distinct functions based on the local environment and signaling cues. Exercise has been shown to drive macrophage polarization from a pro-inflammatory M1 phenotype towards an anti-inflammatory M2 phenotype in numerous tissues, but remains uninvestigated in the peripheral nervous system. METHODS The purpose of our study was to identify how exercise affects macrophage polarization, motor and sensory function, and neuroregeneration following sciatic nerve crush. Male and female C57BL/6 mice underwent sciatic nerve crush injury and were then given access to running wheels (exercised) or not given access to running wheels (sedentary) for 4 weeks. Analysis included behavioral assessments, anatomical studies, and in vitro studies. RESULTS >Exercised mice ran an average of 2.9 km per night. Injured exercised mice were protected from the development of thermal hyperalgesia. Exercised mice had fewer paw slips on beam walk testing compared to sedentary mice. No differences were measured in mechanical sensitivity or motor coordination and balance. Motor nerve conduction velocities from injured exercised animals were significantly higher than injured sedentary animals suggesting improved nerve recovery with exercise. Injured sciatic nerves from exercised mice demonstrated increased M2 macrophages compared to sciatic nerves from injured sedentary mice. The behavioral changes and altered macrophage polarization correlated with increased epidermal nerve fiber density, improved myelination, and increased in vitro neurite outgrowth from injured exercised animals. CONCLUSION Exercise alters macrophage polarization towards an anti-inflammatory phenotype which improves repair and recovery of the injured peripheral nerve.

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Presence and activation of pro-inflammatory macrophages are associated with CRYAB expression in vitro and after peripheral nerve injury

Journal of Neuroinflammation ◽

10.1186/s12974-021-02108-z ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Erin-Mai F. Lim ◽

Vahid Hoghooghi ◽

Kathleen M. Hagen ◽

Kunal Kapoor ◽

Ariana Frederick ◽

...

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Sciatic Nerve Crush ◽

Nerve Crush ◽

Cytokines And Chemokines ◽

Inflammatory Macrophages ◽

Nerve Crush Injury

Abstract Background Inflammation constitutes both positive and negative aspects to recovery following peripheral nerve injury. Following damage to the peripheral nervous system (PNS), immune cells such as macrophages play a beneficial role in creating a supportive environment for regrowing axons by phagocytosing myelin and axonal debris. However, a prolonged inflammatory response after peripheral nerve injury has been implicated in the pathogenesis of negative symptoms like neuropathic pain. Therefore, the post-injury inflammation must be carefully controlled to prevent secondary damage while allowing for regeneration. CRYAB (also known as alphaB-crystallin/HSPB5) is a small heat shock protein that has many protective functions including an immunomodulatory role in mouse models of multiple sclerosis, spinal cord injury, and stroke. Because its expression wanes and rebounds in the early and late periods respectively after PNS damage, and CRYAB null mice with sciatic nerve crush injury display symptoms of pain, we investigated whether CRYAB is involved in the immune response following PNS injury. Methods Sciatic nerve crush injuries were performed in age-matched Cryab knockout (Cryab−/−) and wildtype (WT) female mice. Nerve segments distal to the injury site were processed by immunohistochemistry for macrophages and myelin while protein lysates of the nerves were analyzed for cytokines and chemokines using Luminex and enzyme-linked immunosorbent assay (ELISA). Peritoneal macrophages from the two genotypes were also cultured and polarized into pro-inflammatory or anti-inflammatory phenotypes where their supernatants were analyzed for cytokines and chemokines by ELISA and protein lysates for macrophage antigen presenting markers using western blotting. Results We report that (1) more pro-inflammatory CD16/32+ macrophages are present in the nerves of Cryab−/− mice at days 14 and 21 after sciatic nerve crush-injury compared to WT counterparts, and (2) CRYAB has an immunosuppressive effect on cytokine secretion [interleukin (IL)-β, IL-6, IL-12p40, tumor necrosis factor (TNF)-α] from pro-inflammatory macrophages in vitro. Conclusions CRYAB may play a role in curbing the potentially detrimental pro-inflammatory macrophage response during the late stages of peripheral nerve regeneration.

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Reduced Renshaw Recurrent Inhibition after Neonatal Sciatic Nerve Crush in Rats

Neural Plasticity ◽

10.1155/2014/786985 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11

Author(s):

Liang Shu ◽

Jingjing Su ◽

Lingyan Jing ◽

Ying Huang ◽

Yu Di ◽

...

Keyword(s):

Spinal Cord ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Recurrent Inhibition ◽

Crush Injury ◽

Sciatic Nerve Crush ◽

Nerve Crush ◽

Nerve Crush Injury

Renshaw recurrent inhibition (RI) plays an important gated role in spinal motion circuit. Peripheral nerve injury is a common disease in clinic. Our current research was designed to investigate the change of the recurrent inhibitory function in the spinal cord after the peripheral nerve crush injury in neonatal rat. Sciatic nerve crush was performed on 5-day-old rat puppies and the recurrent inhibition between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes (MSR) elicited from the sectioned dorsal roots and recorded either from the LG-S and MG nerves by antidromic stimulation of the synergist muscle nerve. Our results demonstrated that the MSR recorded from both LG-S or MG nerves had larger amplitude and longer latency after neonatal sciatic nerve crush. The RI in both LG-S and MG motoneuron pools was significantly reduced to virtual loss (15–20% of the normal RI size) even after a long recovery period upto 30 weeks after nerve crush. Further, the degree of the RI reduction after tibial nerve crush was much less than that after sciatic nerve crush indicatig that the neuron-muscle disconnection time is vital to the recovery of the spinal neuronal circuit function during reinnervation. In addition, sciatic nerve crush injury did not cause any spinal motor neuron loss but severally damaged peripheral muscle structure and function. In conclusion, our results suggest that peripheral nerve injury during neonatal early development period would cause a more sever spinal cord inhibitory circuit damage, particularly to the Renshaw recurrent inhibition pathway, which might be the target of neuroregeneration therapy.

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Cinnamaldehyde Enhanced Functional Recovery after Sciatic Nerve Crush Injury in Rats

Cells Tissues Organs ◽

10.1159/000507016 ◽

2020 ◽

Vol 209 (1) ◽

pp. 43-53 ◽

Cited By ~ 2

Author(s):

Zohreh Jahromi ◽

Fahimeh Mohammadghasemi ◽

Farshad Moharrami Kasmaie ◽

Arash Zaminy

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Functional Recovery ◽

Crush Injury ◽

Vehicle Group ◽

Sciatic Nerve Crush ◽

Nerve Crush ◽

Clinical Issue ◽

Study Results

Peripheral nerve injury is a common clinical issue induced by trauma, tumor, and damage caused by treatment. Such factors create chemical and inflammatory alterations at the injury site, which increase nerve deterioration. Thus, minimizing these modifications can lead to nerve protection after injury. The present study sought to evaluate the possible improvement in nerve regeneration and enhancement of functional outcomes by cinnamaldehyde (Cin) administration following sciatic nerve crush in a rat model. Rats (n = 48) were distributed into 6 groups, including sham, injury, DMSO (vehicle group), and Cin groups (10, 30, and 90 mg/kg/day). Using small hemostatic forceps, crush injury was induced in the left sciatic nerve. Thereafter, Cin was administered for 28 successive days. Weekly records were taken for sciatic functional index (SFI) measurements. Further assessments including electrophysiological and histomorphometric evaluations, gastrocnemius muscle wet weight measurements, and estimation of the serum total oxidant status were performed. According to the results, Cin could accelerate sciatic nerve recovery after crush injury, and the dose of 30 mg/kg/day of Cin had better impacts on SFI recovery, muscle mass ratio, and myelin content. The current research demonstrated that Cin positively affects peripheral nerve restoration. Therefore, Cin therapy could be considered as a potential treatment method for peripheral nerve regeneration and its functional recovery. However, more investigations are required to further validate the study results and evaluate the optimal dose of Cin.

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Neuroprotective Effect of Nypa fruticans Wurmb by Suppressing TRPV1 Following Sciatic Nerve Crush Injury in a Rat

Nutrients ◽

10.3390/nu12092618 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2618

Author(s):

Mi-Sun Kang ◽

Gil-Hyun Lee ◽

Go-Eun Choi ◽

Hae-Gyung Yoon ◽

Kyung-Yae Hyun

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Functional Recovery ◽

Treated Group ◽

Crush Injury ◽

Sciatic Nerve Crush ◽

Neuroprotective Effects ◽

Nerve Crush ◽

Nypa Fruticans ◽

Nerve Crush Injury

Peripheral nerve injury can result in severe functional impairment and decreased quality of life due to loss of sensory and motor function. Nypa fruticans wurmb (NF) has been used in diverse folk remedies in East Asia. We have previously shown that Nypa fruticans wurmb extract has antinociceptive and anti-inflammatory effects by suppressing TRPV1 in the sciatic nerve injury. The present study investigated the effects of NF on the control of TRPV1 in relation to neuroprotective effects of a sciatic nerve crush injury. To evaluate the neuroprotective effects, an animal behavior test and a physiological function test were performed. Functional recovery and nerve recovery were improved in the NF and NF + SB (SB366791; TRPV1 antagonist) treated group. In the histomorphology evaluation, the neuronal regenerative effect of NF on the injured sciatic nerve was confirmed via hematoxylin and eosin (H&E) staining. In this study, the NF and NF + SB treated group showed neuroprotective and functional recovery effects from the sciatic nerve crush injury. Furthermore, the expression of NF-κB and iNOS showed a significantly suppressive effect on NF (p < 0.01), SB (p < 0.01), and NF + SB (p < 0.01) treated group at the 7th and 14th day compared to the vehicle group. This study confirmed the neuroprotective effects of NF on suppressing TRPV1 in a sciatic nerve crush injury. The findings of this study establish the effect of NF as a neurotherapeutic agent to protect the peripheral nerve after a sciatic nerve crush injury.

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Dexamethasone Enhanced Functional Recovery after Sciatic Nerve Crush Injury in Rats

BioMed Research International ◽

10.1155/2015/627923 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Xinhong Feng ◽

Wei Yuan

Keyword(s):

Sciatic Nerve ◽

Nerve Injury ◽

Muscle Mass ◽

Functional Recovery ◽

Rat Model ◽

Gastrocnemius Muscle ◽

Sciatic Nerve Crush ◽

Mass Ratio ◽

Nerve Crush ◽

Nerve Crush Injury

Dexamethasone is currently used for the treatment of peripheral nerve injury, but its mechanisms of action are not completely understood. Inflammation/immune response at the site of nerve lesion is known to be an essential trigger of the pathological changes that have a critical impact on nerve repair and regeneration. In this study, we observed the effects of various doses of dexamethasone on the functional recovery after sciatic nerve crush injury in a rat model. Motor functional recovery was monitored by walking track analysis and gastrocnemius muscle mass ratio. The myelinated axon number was counted by morphometric analysis. Rats administered dexamethasone by local intramuscular injection had a higher nerve function index value, increased gastrocnemius muscle mass ratio, reduced Wallerian degeneration severity, and enhanced regenerated myelinated nerve fibers. Immunohistochemical analysis was performed for CD3 expression, which is a marker for T-cell activation, and infiltration in the sciatic nerve. Dexamethasone-injected rats had fewer CD3-positive cells compared to controls. Furthermore, we found increased expression of GAP-43, which is a factor associated with development and plasticity of the nervous system, in rat nerves receiving dexamethasone. These results provide strong evidence that dexamethasone enhances sciatic nerve regeneration and function recovery in a rat model of sciatic nerve injury through immunosuppressive and potential neurotrophic effects.

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Magnetic Resonance Imaging as a Biomarker in Rodent Peripheral Nerve Injury Models Reveals an Age-Related Impairment of Nerve Regeneration

Scientific Reports ◽

10.1038/s41598-019-49850-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Elisa Giorgetti ◽

Michael Obrecht ◽

Marie Ronco ◽

Moh Panesar ◽

Christian Lambert ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Magnetization Transfer Ratio ◽

Sciatic Nerve Crush ◽

Resonance Imaging ◽

Nerve Crush

Abstract Assessment of myelin integrity in peripheral nerve injuries and pathologies has largely been limited to post-mortem analysis owing to the difficulty in obtaining biopsies without affecting nerve function. This is further encumbered by the small size of the tissue and its location. Therefore, the development of robust, non-invasive methods is highly attractive. In this study, we used magnetic resonance imaging (MRI) techniques, including magnetization transfer ratio (MTR), to longitudinally and non-invasively characterize both the sciatic nerve crush and lysolecithin (LCP) demyelination models of peripheral nerve injury in rodents. Electrophysiological, gene expression and histological assessments complemented the extensive MRI analyses in young and aged animals. In the nerve crush model, MTR analysis indicated a slower recovery in regions distal to the site of injury in aged animals, as well as incomplete recovery at six weeks post-crush when analyzing across the entire nerve surface. Similar regional impairments were also found in the LCP demyelination model. This research underlines the power of MTR for the study of peripheral nerve injury in small tissues such as the sciatic nerve of rodents and contributes new knowledge to the effect of aging on recovery after injury. A particular advantage of the approach is the translational potential to human neuropathies.

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Characterization of Neuronal Death and Functional Deficits following Nerve Injury during the Early Postnatal Developmental Period in Rats

Developmental Neuroscience ◽

10.1159/000368769 ◽

2015 ◽

Vol 37 (1) ◽

pp. 66-77 ◽

Cited By ~ 9

Author(s):

Stephen W.P. Kemp ◽

Cameron D. Chiang ◽

Edward H. Liu ◽

Matthew D. Wood ◽

Michael P. Willand ◽

...

Keyword(s):

Sciatic Nerve ◽

Nerve Injury ◽

Sensory Neuron ◽

Functional Recovery ◽

Neuronal Death ◽

Developmental Period ◽

Sciatic Nerve Crush ◽

Distal Stump ◽

Muscle Twitch ◽

Nerve Crush

In contrast to adult rat nerve injury models, neonatal sciatic nerve crush leads to massive motor and sensory neuron death. Death of these neurons results from both the loss of functional contact between the nerve terminals and their targets, and the inability of immature Schwann cells in the distal stump of the injured nerve to sustain regeneration. However, current dogma holds that little to no motoneuron death occurs in response to nerve crush at postnatal day 5 (P5). The purpose of the current study was to fully characterize the extent of motor and sensory neuronal death and functional recovery following sciatic nerve crush at mid-thigh level in rats at postnatal days 3-30 (P3-P30), and then compare this to adult injured animals. Following nerve crush at P3, motoneuron numbers were reduced to 35% of that of naïve uninjured animals. Animals in the P5 and P7 group also displayed statistically fewer motoneurons than naïve animals. Animals that were injured at P30 or earlier displayed statistically lower sensory neuron counts in the dorsal root ganglion than naïve controls. Surprisingly, complete behavioral recovery was observed exclusively in the P30 and adult injured groups. Similar results were observed in muscle twitch/tetanic force analysis, motor unit number estimation and wet muscle weights. Rats in both the P5 and P7 injury groups displayed significant neuronal death and impaired functional recovery following injury, challenging current dogma and suggesting that severe deficits persist following nerve injury during this early postnatal developmental period. These findings have important implications concerning the timing of neonatal nerve injury in rats.

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Circ-Spidr enhances axon regeneration after peripheral nerve injury

Cell Death and Disease ◽

10.1038/s41419-019-2027-x ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 3

Author(s):

Susu Mao ◽

Tao Huang ◽

Yuanyuan Chen ◽

Longxiang Shen ◽

Shuoshuo Zhou ◽

...

Keyword(s):

Nervous System ◽

Sciatic Nerve ◽

Nerve Injury ◽

Axon Regeneration ◽

Neuronal Injury ◽

Circular Rnas ◽

Sciatic Nerve Crush ◽

Drg Neurons ◽

Nerve Crush

Abstract Accumulating evidence suggests that circular RNAs (circRNAs) are abundant and play critical roles in the nervous system. However, their functions in axon regeneration after neuronal injury are unclear. Due to its robust regeneration capacity, peripheral nervous system is ideal for seeking the regulatory circRNAs in axon regeneration. In the present work, we obtained an expression profile of circRNAs in dorsal root ganglions (DRGs) after rat sciatic nerve crush injury by RNA sequencing (RNA-Seq) and found the expression level of circ-Spidr was obviously increased using quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, circ-Spidr was proved to be a circular RNA enriched in the cytoplasm of DRG neurons. Through in vitro and in vivo experiments, we determined that down-regulation of circ-Spidr could suppress axon regeneration of DRG neurons after sciatic nerve injury partially through modulating PI3K-Akt signaling pathway. Together, our results reveal a crucial role for circRNAs in regulating axon regeneration after neuronal injury which may further serve as a potential therapeutic avenue for neuronal injury repair.

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