Figure 2 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Gastrocnemius muscle evaluation by 1 week CCI. (A,C) Multiple time point analysis of gastrocnemius muscle at post nerve release day 0, 3, 7, 14 and 28 (L: left injured side; R: right uninjured side). Left gastrocnemius muscle weight demonstrated significant decrease till post release day 14, with recovery at day 28 after nerve release. (Scale bar: 1 cm. Data was presented with mean ± standard deviation, *** indicated p < 0.001, **** indicated p < 0.0001, ns indicated no significant difference) (B,D) Histology of affected side muscle fiber demonstrated decrease of left muscle fiber surface area from day 0 to day 14, with increase at day 28 after nerve release. (Scale bar: 50 mm. Data was presented with mean ± standard deviation).
Source publication
Peripheral compressive neuropathy causes significant neuropathic pain, muscle weakness and prolong neuroinflammation. Surgical decompression remains the gold standard of treatment but the outcome is suboptimal with a high recurrence rate. From mechanical compression to chemical propagation of the local inflammatory signals, little is known about th...
Contexts in source publication
Context 1
... on the model of CCI for 1 week (Figure 1), the influence of muscle mass after nerve release was also validated. After nerve release, the left gastrocnemius muscle weight post-release was reduced significantly from day 0 to day 14, with recovery at day 28 (Figures 2A,C). The surface area of left injured gastrocnemius muscle fiber also revealed significant atrophy from day 0 to 14, with recovery at day 28 after nerve release ( Figures 2B,D). ...
Context 2
... nerve release, the left gastrocnemius muscle weight post-release was reduced significantly from day 0 to day 14, with recovery at day 28 (Figures 2A,C). The surface area of left injured gastrocnemius muscle fiber also revealed significant atrophy from day 0 to 14, with recovery at day 28 after nerve release ( Figures 2B,D). (A) Animal model of chronic constriction injury over ipsilateral sciatic nerve. ...
Context 3
... on the model of CCI for 1 week (Figure 1), the influence of muscle mass after nerve release was also validated. After nerve release, the left gastrocnemius muscle weight post-release was reduced significantly from day 0 to day 14, with recovery at day 28 (Figure 2A,C). The surface area of left injured gastrocnemius muscle fiber also revealed significant atrophy from day 0 to 14, with recovery at day 28 after nerve release ( Figure 2B,D). ...
Context 4
... nerve release, the left gastrocnemius muscle weight post-release was reduced significantly from day 0 to day 14, with recovery at day 28 (Figure 2A,C). The surface area of left injured gastrocnemius muscle fiber also revealed significant atrophy from day 0 to 14, with recovery at day 28 after nerve release ( Figure 2B,D). ol. ...
Context 5
... staining of NF-200 and S100β in the injured nerve distal to the nerve injury site revealed a significant decrease in myelinated axons from day 0 to 14 post-release ( Figure 3). Increase in remyelinated axons was apparent on day 28, which correlated with the recovery of muscle weight and muscle fiber surface area on day 28 ( Figure 2C,D). ...
Context 6
... 2021, 22, x FOR PEER REVIEW 5 of 18 apparent on day 28, which correlated with the recovery of muscle weight and muscle fiber surface area on day 28 ( Figures 2C,D). Figure 3. Immunohistochemical staining of injured sciatic nerve for axon myelination. ...
Context 7
... this study, when the controllable mechanical compression was applied for 1 week, release of suture could not reverse the neurologic deficit, and the mechanical allodynia persisted ( Figure 1C). The relative muscle weight and surface area also demonstrated progressive loss without significant recovery on day 28 post-nerve release (Figure 2). From the present evidence, 1 week nerve constriction injury is sufficient to induce irreversible mechanical allodynia and significant muscle atrophy, even after nerve release. ...
Context 8
... day 28, the injured nerve returned to its original gross appearance without any signs of swelling nor perineurial fibrosis. Double staining of the nerve demonstrated partial remyelination of axons on day 28, which was compatible with the recovery of muscle mass (Figure 2). Similar findings were reported by Hu et al., demonstrating that axon remyelination was observed 6 weeks after nerve decompression in chronic sciatic nerve compression [22]. ...
Citations
... A total of 12 rats in the injured group were used for the chronic constriction injury (CCI) model on the rat sciatic nerve by computer monitoring of controllable forces (6 g string tension). A week later, the compressive neuropathy of the modi ed CCI model had signi cant and persistent mechanical allodynia and increased neuroin ammation, following the protocol established in our previous studies [19,20]. The left sciatic nerve was dissected from the circumambient tissues and exposed at the middle level of the thigh. ...
... To investigate the therapeutic effects of TENS for neuropathic pain in peripheral compressive neuropathy, a modi ed CCI model on rat sciatic nerve was utilized according to our previous researches [19,20]. Persistent mechanical allodynia was reproducibly induced at 1 week of the unilateral nerve constriction injury (Fig. 1A). ...
A challenging complication in patients with peripheral compressive neuropathy is neuropathic pain. Excessive neuroinflammation and neuropeptide buildup at the injury site worsen neuropathic pain and impair function. Currently, non-invasive modulation like transcutaneous electrical nerve stimulation (TENS) showed therapeutic promise with positive results. However, underlying regulatory molecular mechanism for peripheral neuropathic pain remains complex and unexplored. This study aimed to validate the therapeutic effect of ultrahigh frequency (UHF)-TENS in chronic constriction injury of rat sciatic nerve. The efficacy and safety of UHF-TENS were examined including mechanistical exploration. Alleviation of mechanical allodynia was achieved through the application of UHF-TENS, which lasted for 3 days for a one-session therapy, without additional damage on the myelinated axon structure. Significant reduction of pain-related neuropeptides, MEK, c-Myc, c-FOS, COX2, and substance P, were observed in the injured DRG neurons. RNA sequencing of differential gene expression of the sensory neurons revealed a significant downregulation in Cables, Pik3r1, Vps4b, Tlr7, and Ezh2 after nerve injury, while upregulation was observed in Nfkbie and Cln3. UHF-TENS effectively and safely relieved neuropathic pain without causing further nerve damage. The decreased production of pain-related neuropeptides within the DRG neurons provided the therapeutic benefit. Possible molecular mechanisms by UHF-TENS might result from the modulation of the NF-κB complex, toll-like receptor-7, and phosphoinositide 3-kinase/Akt signaling in sensory neurons. This results suggest the neuromodulatory effects of UHF-TENS in rat sciatic nerve chronic constriction injury, in terms of alleviation of neuropathic pain, amelioration of pain-related neuropeptides, and regulation of neuroinflammatory gene expression. In combination with related molecular medication, UHF-TENS would be a new modality to potentiate the treatment of neuropathic pain in the future.
... The Schwann cells then form a Büngner band-a substrate for regenerating axons-and remyelinate newly formed axons. This series of repair processes requires an inflammatory response, which is activated 3-7 d after PNI (Chen et al, 2021). Inhibition of the inflammatory response via knockout of toll-like receptor (TLR)2 and TLR4 or interleukin (IL)-6 results in reduced macrophage accumulation and a delay in myelin debris clearance and axon regeneration (Zhang et al, 2000;Boivin et al, 2007). ...
Although inflammation is indispensable for the repair process in Wallerian degeneration (WD), the role of neutrophils in the WD repair process remains unclear. After peripheral nerve injury, neutrophils accumulate at the epineurium but not the parenchyma in the WD region because of the blood–nerve barrier. An increase or decrease in the number of neutrophils delayed or promoted macrophage infiltration from the epineurium into the parenchyma and the repair process in WD. Abundant neutrophil extracellular traps (NETs) were formed around neutrophils, and its inhibition dramatically increased macrophage infiltration into the parenchyma. Furthermore, inhibition of either MIF or its receptor, CXCR4, in neutrophils decreased NET formation, resulting in enhanced macrophage infiltration into the parenchyma. Moreover, inhibiting MIF for just 2 h after peripheral nerve injury promoted the repair process. These findings indicate that neutrophils delay the repair process in WD from outside the parenchyma by inhibiting macrophage infiltration via NET formation and that neutrophils, NETs, MIF, and CXCR4 are therapeutic targets for peripheral nerve regeneration.
... Sluggish axonal regrowth often leads to failure of the nerve to reinnervate the target tissue and restore function [11]. The chronic constriction injury model has also shown that sustained levels of pro-inflammatory cytokines (TNFα and IL-1β) and persistent infiltration of macrophages result in neuropathy and muscle weakness [12]. As a result, immune modulation has emerged as a therapeutic target to improve regeneration by regulating inflammation [13,14]. ...
The failure of peripheral nerve regeneration is often associated with the inability to generate a permissive molecular and cellular microenvironment for nerve repair. Autologous therapies, such as platelet-rich plasma (PRP) or its derivative platelet-rich growth factors (PRGF), may improve peripheral nerve regeneration via unknown mechanistic roles and actions in macrophage polarization. In the current study, we hypothesize that excessive and prolonged inflammation might result in the failure of pro-inflammatory M1 macrophage transit to anti-inflammatory M2 macrophages in large nerve defects. PRGF was used in vitro at the time the unpolarized macrophages (M0) macrophages were induced to M1 macrophages to observe if PRGF altered the secretion of cytokines and resulted in a phenotypic change. PRGF was also employed in the nerve conduit of a rat sciatic nerve transection model to identify alterations in macrophages that might influence excessive inflammation and nerve regeneration. PRGF administration reduced the mRNA expression of tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and IL-6 in M0 macrophages. Increased CD206 substantiated the shift of pro-inflammatory cytokines to the M2 regenerative macrophage. Administration of PRGF in the nerve conduit after rat sciatic nerve transection promoted nerve regeneration by improving nerve gross morphology and its targeted gastrocnemius muscle mass. The regenerative markers were increased for regrown axons (protein gene product, PGP9.5), Schwann cells (S100β), and myelin basic protein (MBP) after 6 weeks of injury. The decreased expression of TNFα, IL-1β, IL-6, and CD68+ M1 macrophages indicated that the inflammatory microenvironments were reduced in the PRGF-treated nerve tissue. The increase in RECA-positive cells suggested the PRGF also promoted angiogenesis during nerve regeneration. Taken together, these results indicate the potential role and clinical implication of autologous PRGF in regulating inflammatory microenvironments via macrophage polarization after nerve transection.
... The CCI model is based on the unilateral loose ligation of the sciatic nerve, which corresponds to the pathophysiological properties of chronic neuropathic pain in humans (16). Ligation knots are placed on the sciatic nerve to induce chronic nerve injury (17)(18)(19). However, some studies reported the alleviation of symptoms after 2-4 weeks (20), and Urban et al. reported that they rarely observed signs of pain (21). ...
... The CCI animal model is a well-established neuropathic pain model reported previously (17)(18)(19) and is particularly useful for quantitative assessment of the therapeutic efficacy of cell transplantation on chronic neuropathic pain. To apply a suitable CCI animal model for cell therapy, we first validated a ligation-knot-based constriction injury generated by one, two, or four ligations on the partial sciatic nerve of the right hindlimb ( Figure 1A). ...
... The CCI model is a simple means of replicating chronic pain, although the histological and behavioral results of nerve ligation vary (17)(18)(19). Therefore, it is necessary to examine the ligations regarding the effects of consistent compressive pain. ...
Chronic neuropathic pain is caused by dysfunction of the peripheral nerves associated with the somatosensory system. Mesenchymal stem cells (MSCs) have attracted attention as promising cell therapeutics for chronic pain; however, their clinical application has been hampered by the poor in vivo survival and low therapeutic efficacy of transplanted cells. Increasing evidence suggests enhanced therapeutic efficacy of spheroids formed by three-dimensional culture of MSCs. In the present study, we established a neuropathic pain murine model by inducing a chronic constriction injury through ligation of the right sciatic nerve and measured the therapeutic effects and survival efficacy of spheroids. Monolayer-cultured and spheroids were transplanted into the gastrocnemius muscle close to the damaged sciatic nerve. Transplantation of spheroids alleviated chronic pain more potently and exhibited prolonged in vivo survival compared to monolayer-cultured cells. Moreover, spheroids significantly reduced macrophage infiltration into the injured tissues. Interestingly, the expression of mouse-origin genes associated with inflammatory responses, Ccl11/Eotaxin, interleukin 1A, tumor necrosis factor B, and tumor necrosis factor, was significantly attenuated by the administration of spheroids compared to that of monolayer. These results suggest that MSC spheroids exhibit enhanced in vivo survival after cell transplantation and reduced the host inflammatory response through the regulation of main chronic inflammatory response-related genes.
... Previous studies reported that in the CCI-induced neuropathy model, the TNF-α, IL-1β signals, and infiltration of CD68+ inflammatory cells induced a partial decrease after nerve release [207,208]. Our study showed that TNF-α signaling was an essential feature of PNS autoimmunity [209], since TNF-α expression limitation protected against PIN [210,211]. ...
Peripheral nerve injuries significantly impact patients’ quality of life and poor functional recovery. Chitosan–ufasomes (CTS–UFAs) exhibit biomimetic features, making them a viable choice for developing novel transdermal delivery for neural repair. This study aimed to investigate the role of CTS–UFAs loaded with the propranolol HCl (PRO) as a model drug in enhancing sciatica in cisplatin-induced sciatic nerve damage in rats. Hence, PRO–UFAs were primed, embedding either span 20 or 60 together with oleic acid and cholesterol using a thin-film hydration process based on full factorial design (24). The influence of formulation factors on UFAs’ physicochemical characteristics and the optimum formulation selection were investigated using Design-Expert® software. Based on the optimal UFA formulation, PRO–CTS–UFAs were constructed and characterized using transmission electron microscopy, stability studies, and ex vivo permeation. In vivo trials on rats with a sciatic nerve injury tested the efficacy of PRO–CTS–UFA and PRO–UFA transdermal hydrogels, PRO solution, compared to normal rats. Additionally, oxidative stress and specific apoptotic biomarkers were assessed, supported by a sciatic nerve histopathological study. PRO–UFAs and PRO–CTS–UFAs disclosed entrapment efficiency of 82.72 ± 2.33% and 85.32 ± 2.65%, a particle size of 317.22 ± 6.43 and 336.12 ± 4.9 nm, ζ potential of −62.06 ± 0.07 and 65.24 ± 0.10 mV, and accumulatively released 70.95 ± 8.14% and 64.03 ± 1.9% PRO within 6 h, respectively. Moreover, PRO–CTS–UFAs significantly restored sciatic nerve structure, inhibited the cisplatin-dependent increase in peripheral myelin 22 gene expression and MDA levels, and further re-established sciatic nerve GSH and CAT content. Furthermore, they elicited MBP re-expression, BCL-2 mild expression, and inhibited TNF-α expression. Briefly, our findings proposed that CTS–UFAs are promising to enhance PRO transdermal delivery to manage sciatic nerve damage.
... Peripheral nerve injuries (PNI) are mainly caused by surgery and trauma and are common in clinical practice, with 13 to 23 per 1,00,000 people typically suffering from PNI (1)(2)(3)(4). PNI is characterized by complex regeneration mechanisms, poor prognosis, and slow recovery (5)(6)(7)(8)(9), often leading to sensory and motor dysfunction and even lifelong disability, which not only seriously reduces the quality of life of patients but also brings a more serious health care burden to society (10)(11)(12)(13)(14). However, despite the increased understanding of the mechanisms of injury and regeneration, full functional recovery remains unsatisfactory in most patients (15,16). ...
Background
Peripheral nerve injury (PNI) is very common in clinical practice, which often reduces the quality of life of patients and imposes a serious medical burden on society. However, to date, there have been no bibliometric analyses of the PNI field from 2017 to 2021. This study aimed to provide a comprehensive overview of the current state of research and frontier trends in the field of PNI research from a bibliometric perspective.
Methods
Articles and reviews on PNI from 2017 to 2021 were extracted from the Web of Science database. An online bibliometric platform, CiteSpace, and VOSviewer software were used to generate viewable views and perform co-occurrence analysis, co-citation analysis, and burst analysis. The quantitative indicators such as the number of publications, citation frequency, h-index, and impact factor of journals were analyzed by using the functions of “Create Citation Report” and “Journal Citation Reports” in Web of Science Database and Excel software.
Results
A total of 4,993 papers was identified. The number of annual publications in the field remained high, with an average of more than 998 publications per year. The number of citations increased year by year, with a high number of 22,272 citations in 2021. The United States and China had significant influence in the field. Johns Hopkins University, USA had a leading position in this field. JESSEN KR and JOURNAL OF NEUROSCIENCE were the most influential authors and journals in the field, respectively. Meanwhile, we found that hot topics in the field of PNI focused on dorsal root ganglion (DRG) and satellite glial cells (SGCs) for neuropathic pain relief and on combining tissue engineering techniques and controlling the repair Schwann cell phenotype to promote nerve regeneration, which are not only the focus of research now but is also forecast to be of continued focus in the future.
Conclusion
This is the first study to conduct a comprehensive bibliometric analysis of publications related to PNI from 2017 to 2021, whose bibliometric results can provide a reliable source for researchers to quickly understand key information in this field and identify potential research frontiers and hot directions.
... Six different papers matched with the keywords. 23,[34][35][36][37][38] One focuses on spinal and bulbar muscular atrophy 35 and two address SMA. 23,38 Both SMA papers focus on the transcription factor Krüppel-like Factor 15 (KLF15). ...
Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases which are characterized by the loss of motoneurons within the central nervous system. SMA is a monogenic disease caused by reduced levels of the Survival of motoneuron protein, whereas ALS is a multi-genic disease with over 50 identified disease-causing genes and involvement of environmental risk factors. Although these diseases have different causes, they partially share identical phenotypes and pathomechanisms. To analyze and identify functional connections and to get a global overview of altered pathways in both diseases, protein network analyses are commonly used. Here, we used an in silico tool to test for functional associations between proteins that are involved in actin cytoskeleton dynamics, fatty acid metabolism, skeletal muscle metabolism, stress granule dynamics as well as SMA or ALS risk factors, respectively. In network biology, interactions are represented by edges which connect proteins (nodes). Our approach showed that only a few edges are necessary to present a complex protein network of different biological processes. Moreover, Superoxide dismutase 1, which is mutated in ALS, and the actin-binding protein profilin1 play a central role in the connectivity of the aforementioned pathways. Our network indicates functional links between altered processes that are described in either ALS or SMA. These links may not have been considered in the past but represent putative targets to restore altered processes and reveal overlapping pathomechanisms in both diseases.
... Immune mediators, such as IL-1β, are only required during the WD process and are cleared prior to the initiation of nerve reinnervation, which implies that these factors play temporal roles during distinct stages of the process [6]. The balanced expression of TNFα has been shown to promote axonal regeneration, based on the observed effects of TNFα inhibition by the intraperitoneal and epineurial administration of a TNFα antagonist (etanercept) at the time of a crush injury [7,8]. By contrast, chronic and prolonged inflammation caused by peripheral nerve injury can lead to complications, such as neuropathic pain [9]. ...
Background
Epigenetic regulation by histone deacetylases (HDACs) in Schwann cells (SCs) after injury facilitates them to undergo de- and redifferentiation processes necessary to support various stages of nerve repair. Although de-differentiation activates the synthesis and secretion of inflammatory cytokines by SCs to initiate an immune response during nerve repair, changes in either the timing or duration of prolonged inflammation mediated by SCs can affect later processes associated with repair and regeneration. Limited studies have investigated the regulatory processes through which HDACs in SCs control inflammatory cytokines to provide a favorable environment for peripheral nerve regeneration.
Methods
We employed the HDAC inhibitor (HDACi) sodium phenylbutyrate (PBA) to address this question in an in vitro RT4 SC inflammation model and an in vivo sciatic nerve transection injury model to examine the effects of HDAC inhibition on the expression of pro-inflammatory cytokines. Furthermore, we assessed the outcomes of suppression of extended inflammation on the regenerative potential of nerves by assessing axonal regeneration, remyelination, and reinnervation.
Results
Significant reductions in lipopolysaccharide (LPS)-induced pro-inflammatory cytokine (tumor necrosis factor-α [TNFα]) expression and secretion were observed in vitro following PBA treatment. PBA treatment also affected the transient changes in nuclear factor κB (NFκB)-p65 phosphorylation and translocation in response to LPS induction in RT4 SCs. Similarly, PBA mediated long-term suppressive effects on HDAC3 expression and activity. PBA administration resulted in marked inhibition of pro-inflammatory cytokine secretion at the site of transection injury when compared with that in the hydrogel control group at 6-week post-injury. A conducive microenvironment for axonal regrowth and remyelination was generated by increasing expression levels of protein gene product 9.5 (PGP9.5) and myelin basic protein (MBP) in regenerating nerve tissues. PBA administration increased the relative gastrocnemius muscle weight percentage and maintained the intactness of muscle bundles when compared with those in the hydrogel control group.
Conclusions
Suppressing the lengthened state of inflammation using PBA treatment favors axonal regrowth and remyelination following nerve transection injury. PBA treatment also regulates pro-inflammatory cytokine expression by inhibiting the transcriptional activation of NFκB-p65 and HDAC3 in SCs in vitro.
The peripheral nerve injury (PNI) affects the morphology of the whole locomotor
apparatus, which can reach the myotendinous junction (MTJ) interface. In the injury
condition, the skeletal muscle satellite cells (SC) are triggered, activated, and proliferated to repair their structure, and in the MTJ, the telocytes (TC) are associated to support the interface with the need for remodeling; in that way, these cells can be associated with SC. The study aimed to describe the SC and TC relationship after PNI at the MTJ. Sixteen adult Wistar rats were divided into Control Group (C, n = 8) and PNI Group (PNI, n = 8), PNI was performed by the constriction of the sciatic nerve. The samples were processed for transmission electron microscopy and immunostaining analysis. In the C group was evidenced the arrangement of sarcoplasmic evaginations and invaginations, the support collagen layer with a TC inside it, and an SC through vesicles internally and externally to then. In the PNI group were observed the disarrangement of invaginations and evaginations and sarcomeres degradation at MTJ, as the disposition of telopodes adjacent and in contact to the SC with extracellular vesicles and exosomes in a characterized paracrine activity. These findings can determine a link between the TCs and the SCs at the MTJ remodeling.
A challenging complication in patients with peripheral compressive neuropathy is neuropathic pain. Excessive neuroinflammation at the injury site worsens neuropathic pain and impairs function. Currently, non-invasive modulation techniques like transcutaneous electrical nerve stimulation (TENS) have shown therapeutic promise with positive results. However, the underlying regulatory molecular mechanism for pain relief remains complex and unexplored. This study aimed to validate the therapeutic effect of ultrahigh frequency (UHF)-TENS in chronic constriction injury of the rat sciatic nerve. Alleviation of mechanical allodynia was achieved through the application of UHF-TENS, lasting for 3 days after one session of therapy and 4 days after two sessions, without causing additional damage to the myelinated axon structure. The entire tissue collection schedule was divided into four time points: nerve exposure surgery, 7 days after nerve ligation, and 1 and 5 days after one session of UHF therapy. Significant reductions in pain-related neuropeptides, MEK, c-Myc, c-FOS, COX2, and substance P, were observed in the injured DRG neurons after UHF therapy. RNA sequencing of differential gene expression in sensory neurons revealed significant downregulation in Cables, Pik3r1, Vps4b, Tlr7, and Ezh2 after UHF therapy, while upregulation was observed in Nfkbie and Cln3. UHF-TENS effectively and safely relieved neuropathic pain without causing further nerve damage. The decreased production of pain-related neuropeptides within the DRG provided the therapeutic benefit. Possible molecular mechanisms behind UHF-TENS may result from the modulation of the NF-κB complex, toll-like receptor-7, and phosphoinositide 3-kinase/Akt signaling pathways. These results suggest the neuromodulatory effects of UHF-TENS in rat sciatic nerve chronic constriction injury, including alleviation of neuropathic pain, amelioration of pain-related neuropeptides, and regulation of neuroinflammatory gene expression. In combination with the regulation of related neuroinflammatory genes, UHF-TENS could become a new modality for enhancing the treatment of neuropathic pain in the future.
