Dynamic regulation of spinal pro-inflammatory cytokine release in the rat in vivo following peripheral nerve injury

Abstract Peripheral nerve injury (PNI) is one of the common clinical injuries which needs to be addressed. Previous studies demonstrated the effectiveness of using biodegradable chitin (CT) conduits small gap tubulization technology as a substitute for traditional epineurial neurorrhaphy. Aiming to improve the effectiveness of CT conduits in repairing PNI, we modified their surface with a DNA-peptide coating. The coating consisted of single strand DNA (ssDNA) and its complementary DNA’-peptide mimics. First, we immobilize ssDNA (DNA1+2) on CT conduits by EDC/NHS method to construct CT/DNA conduits. EDC/NHS was used to activate carboxyl groups of modified ssDNA for direct reaction with primary amines on the chitin via amide bond formation. Then, DNA1’-BDNF+DNA2’-VEGF mimic peptide （RGI+KLT）were bonded to CT/DNA conduits by complementary base pairing principle at room temperature to form CT/RGI+KLT conduits. When the surrounding environment rose to a certain point (37℃), the CT/RGI+KLT conduits achieved sustainable release of DNA’-peptide. In vitro, the CT conduits modified with the DNA-peptide coating promoted the proliferation and secretion of Schwann cells by maintaining their repair state. It also promoted the proliferation of HUVECs and axon outgrowth of DRG explants. In vivo, CT/RGI+KLT conduits promoted regeneration of injured nerves and functional recovery of target muscles, which was facilitated by the synergistic contribution of angiogenesis and neurogenesis. Our research brings DNA and DNA-peptide hybrids into the realm of tissue engineering to repair peripheral nerve injury.

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Localized and Sustained Delivery of Erythropoietin from PLGA Microspheres Promotes Functional Recovery and Nerve Regeneration in Peripheral Nerve Injury

BioMed Research International ◽

10.1155/2015/478103 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Wei Zhang ◽

Yuan Gao ◽

Yan Zhou ◽

Jianheng Liu ◽

Licheng Zhang ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Intraperitoneal Injection ◽

Sustained Delivery ◽

Plga Microspheres ◽

Neuroprotective Effects ◽

Injury Recovery ◽

Daily Intraperitoneal Injection

Erythropoietin (EPO) has been demonstrated to exert neuroprotective effects on peripheral nerve injury recovery. Though daily intraperitoneal injection of EPO during a long period of time was effective, it was a tedious procedure. In addition, only limited amount of EPO could reach the injury sites by general administration, and free EPO is easily degradedin vivo. In this study, we encapsulated EPO in poly(lactide-co-glycolide) (PLGA) microspheres. Bothin vitroandin vivorelease assays showed that the EPO-PLGA microspheres allowed sustained release of EPO within a period of two weeks. After administration of such EPO-PLGA microspheres, the peripheral nerve injured rats had significantly better recovery compared with those which received daily intraperitoneal injection of EPO, empty PLGA microspheres, or saline treatments. This was supported by the functional, electrophysiological, and histological evaluations of the recovery done at week 8 postoperatively. We conclude that sustained delivery of EPO could be achieved by using EPO-PLGA microspheres, and such delivery method could further enhance the recovery function of EPO in nerve injury recovery.

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Nerve Suture Combined With ADSCs Injection Under Real-Time and Dynamic NIR-II Fluorescence Imaging in Peripheral Nerve Regeneration in vivo

Frontiers in Chemistry ◽

10.3389/fchem.2021.676928 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shixian Dong ◽

Sijia Feng ◽

Yuzhou Chen ◽

Mo Chen ◽

Yimeng Yang ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Real Time ◽

Fluorescence Imaging ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Post Injection ◽

Nerve Suture

Peripheral nerve injury gives rise to devastating conditions including neural dysfunction, unbearable pain and even paralysis. The therapeutic effect of current treatment for peripheral nerve injury is unsatisfactory, resulting in slow nerve regeneration and incomplete recovery of neural function. In this study, nerve suture combined with ADSCs injection was adopted in rat model of sciatic nerve injury. Under real-time visualization of the injected cells with the guidance of NIR-II fluorescence imaging in vivo, a spatio-temporal map displaying cell migration from the proximal injection site (0 day post-injection) of the nerve to the sutured site (7 days post-injection), and then to the distal section (14 days post-injection) was demonstrated. Furthermore, the results of electromyography and mechanical pain threshold indicated nerve regeneration and functional recovery after the combined therapy. Therefore, in the current study, the observed ADSCs migration in vivo, electrophysiological examination results and pathological changes all provided robust evidence for the efficacy of the applied treatment. Our approach of nerve suture combined with ADSCs injection in treating peripheral nerve injury under real-time NIR-II imaging monitoring in vivo added novel insights into the treatment for peripheral nerve injury, thus further enhancing in-depth understanding of peripheral nerve regeneration and the mechanism behind.

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In Vivo Nerve-Macrophage Interactions Following Peripheral Nerve Injury

Journal of Neuroscience ◽

10.1523/jneurosci.5225-11.2012 ◽

2012 ◽

Vol 32 (11) ◽

pp. 3898-3909 ◽

Cited By ~ 57

Author(s):

A. F. Rosenberg ◽

M. A. Wolman ◽

C. Franzini-Armstrong ◽

M. Granato

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury

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Incline treadmill exercise suppresses pain hypersensitivity associated with the modulation of pro-inflammatory cytokines and anti-inflammatory cytokine in rats with peripheral nerve injury

Neuroscience Letters ◽

10.1016/j.neulet.2017.02.021 ◽

2017 ◽

Vol 643 ◽

pp. 27-31 ◽

Cited By ~ 6

Author(s):

Kun-Ling Tsai ◽

Po-Ching Huang ◽

Li-Kai Wang ◽

Ching-Hsia Hung ◽

Yu-Wen Chen

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Inflammatory Cytokines ◽

Peripheral Nerve Injury ◽

Inflammatory Cytokine ◽

Treadmill Exercise ◽

Pain Hypersensitivity ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine ◽

Pro Inflammatory Cytokines

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Betacellulin Regulates Peripheral Nerve Regeneration by Affecting Schwann Cell Migration and Axon Elongation

10.21203/rs.3.rs-174606/v1 ◽

2021 ◽

Author(s):

Yaxian Wang ◽

Fuchao Zhang ◽

Yunsong Zhang ◽

Qi Shan ◽

Wei Liu ◽

...

Keyword(s):

Cell Migration ◽

Schwann Cell ◽

Peripheral Nerve ◽

Schwann Cells ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Cultured Cells ◽

Axon Elongation ◽

Schwann Cell Migration

Abstract Background Growth factors execute essential biological functions and affect various physiological and pathological processes, including peripheral nerve injury and regeneration. Our previous sequencing analysis found that betacellulin (Btc), an epidermal growth factor protein family member, showed elevated mRNA expressions in the nerve segment after rat peripheral nerve injury, implying the potential involvement of Btc during peripheral nerve repair. Methods Expression of Btc was examined in Schwann cells. The role of Btc in regulating Schwann cells was investigated by transfecting cultured cells with siRNA segment against Btc or exposed cultured cells with Btc recombinant protein, respectively. The biological functions of Schwann cell-secreted Btc on neurons were also determined. Moreover, the in vivo effect of Btc on Schwann cell migration and axon elongation after rat sciatic nerve injury were further evaluated.Results Immunostaining images and ELISA readings showed Btc was present in and secreted by Schwann cells. Transwell migration and wound healing observations showed that siRNA against Btc impeded Schwann cell migration while exogenous Btc advanced Schwann cell migration. Besides the regulating effect on Schwann cell phenotype, Btc secreted by Schwann cells might influence neuron behavior and affect axon length. In vivo evidence showed that Btc enhanced axonal regrowth and nerve regeneration after both rat sciatic nerve crush injury and transection injury. Conclusion Our findings demonstrated Btc-mediated Schwann cell-axon interactions, revealed the essential roles of Btc on Schwann cell migration and axon elongation, and implied the potential application of Btc as a regenerative strategy for treating peripheral nerve injury.

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In vivo USPIO Magnetic Resonance Imaging Shows That Minocycline Mitigates Macrophage Recruitment to a Peripheral Nerve Injury

Molecular Pain ◽

10.1186/1744-8069-8-49 ◽

2012 ◽

Vol 8 ◽

pp. 1744-8069-8-49 ◽

Cited By ~ 15

Author(s):

Pejman Ghanouni ◽

Deepak Behera ◽

Jin Xie ◽

Xiaoyuan Chen ◽

Michael Moseley ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Resonance Imaging ◽

Macrophage Recruitment

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BDNF produced by cerebral microglia promotes cortical plasticity and pain hypersensitivity after peripheral nerve injury

PLoS Biology ◽

10.1371/journal.pbio.3001337 ◽

2021 ◽

Vol 19 (7) ◽

pp. e3001337

Author(s):

Lianyan Huang ◽

Jianhua Jin ◽

Kai Chen ◽

Sikun You ◽

Hongyang Zhang ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Cortical Plasticity ◽

Conditional Knockout ◽

Normal Density ◽

Pain Hypersensitivity ◽

Functional Changes ◽

Beneficial Effects

Peripheral nerve injury–induced mechanical allodynia is often accompanied by abnormalities in the higher cortical regions, yet the mechanisms underlying such maladaptive cortical plasticity remain unclear. Here, we show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit. Following peripheral nerve injury, microglia in the S1 maintain ramified morphology and normal density but up-regulate the mRNA expression of brain-derived neurotrophic factor (BDNF). Using in vivo two-photon imaging and Cx3cr1CreER;Bdnfflox mice, we show that conditional knockout of BDNF from microglia prevents nerve injury–induced synaptic remodeling and pyramidal neuron hyperactivity in the S1, as well as pain hypersensitivity in mice. Importantly, S1-targeted removal of microglial BDNF largely recapitulates the beneficial effects of systemic BDNF depletion on cortical plasticity and allodynia. Together, these findings reveal a pivotal role of cerebral microglial BDNF in somatosensory cortical plasticity and pain hypersensitivity.

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Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Journal of Neuroinflammation ◽

10.1186/s12974-021-02292-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Jiawei Xu ◽

Jinkun Wen ◽

Lanya Fu ◽

Liqiang Liao ◽

Ying Zou ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Axonal Regeneration ◽

Wallerian Degeneration ◽

Future Application ◽

Injured Nerve

Abstract Background Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury. Methods Immunohistochemistry, Western blotting, H&E staining, and electrophysiology were performed to access the Wallerian degeneration and axonal regeneration after sciatic nerve transection and crush injury in the LyzCre+/−; RhoAflox/flox (cKO) mice or Lyz2Cre+/− (Cre) mice, regardless of sex. Macrophages’ migration and phagocytosis were detected in the injured nerves and the cultured macrophages. Moreover, the expression and potential roles of ROCK and MLCK were also evaluated in the cultured macrophages. Results 1. RhoA was specifically knocked out in macrophages of the cKO mice; 2. The segmentation of axons and myelin, the axonal regeneration, and nerve conduction in the injured nerve were significantly impeded while the myoatrophy was more severe in the cKO mice compared with those in Cre mice; 3. RhoA knockout attenuated the migration and phagocytosis of macrophages in vivo and in vitro; 4. ROCK and MLCK were downregulated in the cKO macrophages while inhibition of ROCK and MLCK could weaken the migration and phagocytosis of macrophages. Conclusions Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.

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