scholarly journals Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury

2021 ◽  
Vol 22 (18) ◽  
pp. 10090
Author(s):  
Jeremy Tsung-Chieh Chen ◽  
Lea Schmidt ◽  
Christina Schürger ◽  
Mohammed K. Hankir ◽  
Susanne M. Krug ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Chronic Constriction Injury ◽  
Neuronal Damage ◽  
Pain Processing ◽  
Central Nervous Systems ◽  
Neuronal Guidance ◽  
Junction Proteins

The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain.

scholarly journals Tumors Provoke Inflammation and Perineural Microlesions at Adjacent Peripheral Nerves

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 320 ◽  
Author(s):  
Jennifer Cohnen ◽  
Lisa Kornstädt ◽  
Lisa Hahnefeld ◽  
Nerea Ferreiros ◽  
Sandra Pierre ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerves ◽  
Neuronal Damage ◽  
Physical Contact ◽  
Melanoma Tumor ◽  
Inflammatory Processes ◽  
Sciatic Nerves ◽  
Tumor Types ◽  
Junction Proteins ◽  
Time Point

Cancer-induced pain occurs frequently in patients when tumors or their metastases grow in the proximity of nerves. Although this cancer-induced pain states poses an important therapeutical problem, the underlying pathomechanisms are not understood. Here, we implanted adenocarcinoma, fibrosarcoma and melanoma tumor cells in proximity of the sciatic nerve. All three tumor types caused mechanical hypersensitivity, thermal hyposensitivity and neuronal damage. Surprisingly the onset of the hypersensitivity was independent of physical contact of the nerve with the tumors and did not depend on infiltration of cancer cells in the sciatic nerve. However, macrophages and dendritic cells appeared on the outside of the sciatic nerves with the onset of the hypersensitivity. At the same time point downregulation of perineural tight junction proteins was observed, which was later followed by the appearance of microlesions. Fitting to the changes in the epi-/perineurium, a dramatic decrease of triglycerides and acylcarnitines in the sciatic nerves as well as an altered localization and appearance of epineural adipocytes was seen. In summary, the data show an inflammation at the sciatic nerves as well as an increased perineural and epineural permeability. Thus, interventions aiming to suppress inflammatory processes at the sciatic nerve or preserving peri- and epineural integrity may present new approaches for the treatment of tumor-induced pain.

Differential Effects of Intrathecally Administered Morphine and Its Interaction with Cholecystokinin-B Antagonist on Thermal Hyperalgesia following Two Models of Experimental Mononeuropathy in the Rat 

1999 ◽  
Vol 90 (5) ◽  
pp. 1382-1391 ◽  
Author(s):  
Tatsuo Yamamoto ◽  
Yoshihiko Sakashita
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Sciatic Nerve Injury ◽  
Morphine Analgesia ◽  
Injury Model ◽  
The Right

Background Cholecystokinin-B receptor activation has been reported to reduce morphine analgesia. Neuropathic pain is thought to be relatively refractory to opioids. One possible mechanisms for a reduced effect of morphine on neuropathic pain is the induction of cholecystokinin in the spinal cord by nerve injury. The authors evaluated the role of the spinal cholecystokinin-B receptor on morphine analgesia in two rat neuropathic pain models: chronic constriction injury and partial sciatic nerve injury. Methods A chronic constriction injury is created by placing four loosely tied ligatures around the right sciatic nerve. A partial sciatic nerve injury was created by tight ligation of one third to one half of the right sciatic nerve. All drugs were injected intrathecally 7 and 11 days after the nerve injury. The effect of the drugs was reflected in the degree of paw withdrawal latency to thermal nociceptive stimulation. The paw withdrawal latencies of injured and uninjured paws were measured 5, 15, 30, and 60 min after the drugs were injected. Results In the chronic constriction injury model, intrathecal morphine increased the paw withdrawal latencies of injured and uninjured paws. PD135158, a cholecystokinin-B receptor antagonist, potentiated the analgesic effect of morphine on injured and uninjured paws. In the partial sciatic nerve injury model, the effect of morphine on the injured paw was less potent than that on the uninjured paw, and PD135158 potentiated the morphine analgesia in the uninjured paw and had only a minor effect on the morphine analgesia in the injured paw. Conclusions The effectiveness of morphine for thermal hyperalgesia after nerve injury depends on the type of nerve injury. The role of the cholecystokinin-B receptor in morphine analgesia in thermal hyperalgesia after nerve injury also depends on the type of nerve injury.

scholarly journals S100ß and fibroblast growth factor-2 are present in cultured Schwann cells and may exert paracrine actions on the peripheral nerve injury

2008 ◽  
Vol 23 (6) ◽  
pp. 555-560 ◽  
Author(s):  
Tatiana Duobles ◽  
Thais de Sousa Lima ◽  
Beatriz de Freitas Azevedo Levy ◽  
Gerson Chadi
Keyword(s):  
Growth Factor ◽  
Sciatic Nerve ◽  
Fibroblast Growth Factor ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Satellite Cells ◽  
Peripheral Nerves ◽  
Fibroblast Growth Factor 2 ◽  
Fibroblast Growth ◽  
Cultured Schwann Cells

PURPOSE: The neurotrophic factor fibroblast growth factor-2 (FGF-2, bFGF) and Ca++ binding protein S100ß are expressed by the Schwann cells of the peripheral nerves and by the satellite cells of the dorsal root ganglia (DRG). Recent studies have pointed out the importance of the molecules in the paracrine mechanisms related to neuronal maintenance and plasticity of lesioned motor and sensory peripheral neurons. Moreover, cultured Schwann cells have been employed experimentally in the treatment of central nervous system lesions, in special the spinal cord injury, a procedure that triggers an enhanced sensorymotor function. Those cells have been proposed to repair long gap nerve injury. METHODS: Here we used double labeling immunohistochemistry and Western blot to better characterize in vitro and in vivo the presence of the proteins in the Schwann cells and in the satellite cells of the DRG as well as their regulation in those cells after a crush of the rat sciatic nerve. RESULTS: FGF-2 and S100ß are present in the Schwann cells of the sciatic nerve and in the satellite cells of the DRG. S100ß positive satellite cells showed increased size of the axotomized DRG and possessed elevated amount of FGF-2 immunoreactivity. Reactive satellite cells with increased FGF-2 labeling formed a ring-like structure surrounding DRG neuronal cell bodies.Reactive S100ß positive Schwann cells of proximal stump of axotomized sciatic nerve also expressed higher amounts of FGF-2. CONCLUSION: Reactive peripheral glial cells synthesizing FGF-2 and S100ß may be important in wound repair and restorative events in the lesioned peripheral nerves.

scholarly journals Role of IL-15 in spinal cord and sciatic nerve after chronic constriction injury: regulation of macrophage and T-cell infiltration

2008 ◽  
Vol 107 (6) ◽  
pp. 1741-1752 ◽  
Author(s):  
D. Gómez-Nicola ◽  
B. Valle-Argos ◽  
M. Suardíaz ◽  
J. S. Taylor ◽  
M. Nieto-Sampedro
Keyword(s):  
Spinal Cord ◽  
T Cell ◽  
Sciatic Nerve ◽  
Chronic Constriction Injury ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals Dynamic effects of TNF-α on synaptic transmission in mice over time following sciatic nerve chronic constriction injury

2013 ◽  
Vol 110 (7) ◽  
pp. 1663-1671 ◽  
Author(s):  
Hongmei Zhang ◽  
Haijun Zhang ◽  
Patrick M. Dougherty
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Synaptic Transmission ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Chronic Constriction Injury ◽  
Synaptic Signaling ◽  
Tnf Α ◽  
Over Time

Nerve injury-induced central sensitization can manifest as an increase in excitatory synaptic transmission and/or as a decrease in inhibitory synaptic transmission in spinal dorsal horn neurons. Cytokines such as tumor necrosis factor-α (TNF-α) are induced in the spinal cord under various injury conditions and contribute to neuropathic pain. In this study we examined the effect of TNF-α in modulating excitatory and inhibitory synaptic input to spinal substantia gelatinosa (SG) neurons over time in mice following chronic constriction injury (CCI) of the sciatic nerve. Whole cell patch-clamp studies from SG neurons showed that TNF-α enhanced overall excitability of the spinal cord early in time following nerve injury 3 days after CCI compared with that in sham control mice. In contrast, the effects of TNF were blunted 14 days after CCI in nerve-injured mice compared with sham surgery mice. Immunohistochemical staining showed that the expression of TNF-α receptor 1 (TNFR1) was increased at 3 days but decreased at 14 days following CCI in the ipsilateral vs. the contralateral spinal cord dorsal horn. These results suggest that TNF-α acting at TNFR1 is important in the development of neuropathic pain by facilitating excitatory synaptic signaling in the acute phases after nerve injury but has a reduced effect on spinal neuron signaling in the later phases of nerve injury-induced pain. Failure of the facilatory effects of TNF-α on excitatory synaptic signaling in the dorsal horn to resolve following nerve injury may be an important component in the transition between acute and chronic pain conditions.

scholarly journals The Role of NLRP3 in Repairing Sciatic Nerve Injury

2019 ◽  
Vol 8 (02) ◽  
pp. 124-129
Author(s):  
Jia Yao ◽  
Zhu Yuzhen ◽  
High Xiao ◽  
Xuan Yang ◽  
Jianzhao Deng ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Injury ◽  
Sciatic Nerve Injury

scholarly journals Ulinastatin Promotes Regeneration of Peripheral Nerves After Sciatic Nerve Injury by Targeting let-7 microRNAs and Enhancing NGF Expression

2020 ◽  
Vol Volume 14 ◽  
pp. 2695-2705
Author(s):  
Jincheng Zhang ◽  
Yingqi Zhang ◽  
Lei Chen ◽  
Zhitao Rao ◽  
Yeqing Sun
Keyword(s):  
Sciatic Nerve ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Sciatic Nerve Injury

Permeability of Injured and Intact Peripheral Nerves and Dorsal Root Ganglia

2006 ◽  
Vol 105 (1) ◽  
pp. 146-153 ◽  
Author(s):  
Stephen E. Abram ◽  
Johnny Yi ◽  
Andreas Fuchs ◽  
Quinn H. Hogan
Keyword(s):  
Spinal Cord ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
Peripheral Nerves ◽  
Dorsal Root ◽  
Intrathecal Injection ◽  
Epidural Injection ◽  
Therapeutic Benefit ◽  
Sodium Fluorescein ◽  
Perineural Injection

Background Nerve injury that produces behavioral changes of allodynia and hyperalgesia in animals is associated with electrophysiologic changes in dorsal root ganglion (DRG) cells. The introduction of drugs into the DRG or the peripheral nerve that alter calcium, sodium, or potassium channel activity may be of therapeutic benefit after nerve injury. For this reason, the authors sought to determine whether drugs that do not ordinarily cross the blood-nerve barrier will enter the DRG after intravenous or regional injection and to determine whether nerve injury alters drug access to DRGs or peripheral nerves. Methods Both intact and spinal nerve-ligated rats were injected with sodium fluorescein by intravenous, intrathecal, peri-DRG, perisciatic, and epidural routes. DRG, sciatic nerve, and spinal cord tissues were harvested and frozen, and histologic sections were analyzed quantitatively for tissue fluorescence. Results In both intact and nerve-injured animals, fluorescein accumulated in DRGs after intravenous, peri-DRG, and epidural injection. There was accumulation in the proximal portion of the ganglion after intrathecal injection. Minimal amounts of fluorescein were found in the sciatic nerve in intact animals after intravenous or perineural injection, but substantial amounts were found in some nerve fascicles in nerve-injured animals after both intravenous and perineural injection. There was almost no fluorescein found in the spinal cord except after intrathecal administration. Conclusions In both intact and nerve-injured animals, fluorescein accumulates freely in the DRG after intravenous, epidural, or paravertebral injection. The sciatic nerve is relatively impermeable to fluorescein, but access by either systemic or regional injection is enhanced after nerve injury.

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