scholarly journals p66shc siRNA-Encapsulated PLGA Nanoparticles Ameliorate Neuropathic Pain Following Spinal Nerve Ligation

Polymers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1014
Author(s):  
Nara Shin ◽  
Hyo Jung Shin ◽  
Yoonyoung Yi ◽  
Jaewon Beom ◽  
Wonhyung Lee ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Caspase 3 ◽  
Adaptor Protein ◽  
Treated Group ◽  
Plga Nanoparticles ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Expression Levels ◽  
Proinflammatory Mediators

p66shc, a member of the shc adaptor protein family, has been shown to participate in regulation of mitochondrial homeostasis, apoptosis, and autophagosome formation. The present study was performed to investigate whether p66shc siRNA-encapsulated poly(d,l-lactic-co-glycolic acid) nanoparticles (p66shc siRNA-PLGA NPs) can attenuate spinal nerve ligation (SNL)-induced neuropathic pain in rats. The SNL-induced pain behavior was decreased in the p66shc siRNA-PLGA NP-treated group compared with the scrambled siRNA-PLGA NP-treated group. In the L5 spinal cord of the p66shc siRNA-PLGA NP-treated group, expression levels of phosphorylated p66shc, cleaved caspase-3, p62, and PINK1, as well as microglial activation, were also decreased. In addition, p66shc knockdown using p66shc siRNA reduced the expression levels of cleaved caspase-3, p62, and PINK1, as well as proinflammatory mediators in the H2O2-treated HT22 neuronal cells. These results suggest that downregulation of p66shc expression in the spinal cord using p66shc siRNA-PLGA NPs could reduce the SNL-induced neuropathic pain by attenuating the SNL-induced aberrant autophagic, mitophagic, and neuroinflammatory processes in rats.

scholarly journals CX3CR1-Targeted PLGA Nanoparticles Reduce Microglia Activation and Pain Behavior in Rats with Spinal Nerve Ligation

2020 ◽  
Vol 21 (10) ◽  
pp. 3469
Author(s):  
Chan Noh ◽  
Hyo Jung Shin ◽  
Seounghun Lee ◽  
Song I Kim ◽  
Yoon-Hee Kim ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Double Emulsion ◽  
Plga Nanoparticles ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Proinflammatory Mediators ◽  
Bv2 Cells ◽  
New Treatment ◽  
Interfering Rna

Activation of CX3CR1 in microglia plays an important role in the development of neuropathic pain. Here, we investigated whether neuropathic pain could be attenuated in spinal nerve ligation (SNL)-induced rats by reducing microglial activation through the use of poly(D,L-lactic-co-glycolic acid) (PLGA)-encapsulated CX3CR1 small-interfering RNA (siRNA) nanoparticles. After confirming the efficacy and specificity of CX3CR1 siRNA, as evidenced by its anti-inflammatory effects in lipopolysaccharide-stimulated BV2 cells in vitro, PLGA-encapsulated CX3CR1 siRNA nanoparticles were synthesized by sonication using the conventional double emulsion (W/O/W) method and administered intrathecally into SNL rats. CX3CR1 siRNA-treated rats exhibited significant reductions in the activation of microglia in the spinal dorsal horn and a downregulation of proinflammatory mediators, as well as a significant attenuation of mechanical allodynia. These data indicate that the PLGA-encapsulated CX3CR1 siRNA nanoparticles effectively reduce neuropathic pain in SNL-induced rats by reducing microglial activity and the expression of proinflammatory mediators. Therefore, we believe that PLGA-encapsulated CX3CR1 siRNA nanoparticles represent a valuable new treatment option for neuropathic pain.

Increased Expression of Cyclooxygenase and Nitric Oxide Isoforms, and Exaggerated Sensitivity to Prostaglandin E2, in the Rat Lumbar Spinal Cord 3 Days after L5–L6 Spinal Nerve Ligation

2006 ◽  
Vol 104 (2) ◽  
pp. 328-337 ◽  
Author(s):  
Darren D. O’Rielly ◽  
Christopher W. Loomis
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Glutamate Release ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Withdrawal Threshold ◽  
Enhanced Sensitivity ◽  
Sham Surgery ◽  
Inducible Nos

Background Spinal prostaglandins seem to be important in the early pathogenesis of experimental neuropathic pain. Here, the authors investigated changes in the expression of cyclooxygenase and nitric oxide synthase (NOS) isoforms in the lumbar, thoracic, and cervical spinal cord and the pharmacologic sensitivity to spinal prostaglandin E2 (PGE2) after L5-L6 spinal nerve ligation (SNL). Methods Male Sprague-Dawley rats, fitted with intrathecal catheters, underwent SNL or sham surgery 3 days before experimentation. Paw withdrawal threshold was monitored for up to 20 days. Immunoblotting, spinal glutamate release, and behavioral testing were examined 3 days after SNL. Results Allodynia (paw withdrawal threshold < or = 4 g) was evident 1 day after SNL and remained stable for 20 days. Paw withdrawal threshold was unchanged (P > 0.05) from baseline (> 15 g) after sham surgery except for a small but significant decrease on day 20. Cyclooxygenase 2, neuronal NOS, and inducible NOS were significantly increased in the ipsilateral lumbar dorsal horn after SNL. Expression in the contralateral dorsal horn and ventral horns (lumbar segments) or bilaterally (thoracic and cervical segments) was unchanged from sham controls. This was accompanied by a significant decrease in both the EC50 of PGE2-evoked glutamate release and the ED50 of PGE2 on brush-evoked allodynia. Enhanced sensitivity to PGE2 was localized to lumbar segments of SNL animals and attenuated by SC-51322 or S(+)-ibuprofen, but not R(-)-ibuprofen (100 mum). Conclusion The increased expression of cyclooxygense-2, neuronal NOS, and inducible NOS and the enhanced sensitivity to PGE2 in spinal segments affected by SNL support the hypothesis that spinal prostanoids play an early pathogenic role in experimental neuropathic pain.

Cyclooxygenase-1 in the Spinal Cord Is Altered after Peripheral Nerve Injury

2003 ◽  
Vol 99 (5) ◽  
pp. 1175-1179 ◽  
Author(s):  
Xiaoying Zhu ◽  
James C. Eisenach
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Male Rats ◽  
Dependent Manner ◽  
Cyclooxygenase 1 ◽  
Cox 1

Background The mechanisms underlying neuropathic pain are incompletely understood and its treatment is often unsatisfactory. Spinal cyclooxygenase-2 (COX-2) expression is upregulated after peripheral inflammation, associated with spinal prostaglandin production leading to central sensitization, but the role of COX isoenzymes in sensitization after nerve injury is less well characterized. The current study was undertaken to determine whether COX-1 was altered in this model. Methods Male rats underwent partial sciatic nerve transsection (PSNT) or L5-L6 spinal nerve ligation (SNL). Four weeks after PSNT and 4 h, 4 days, or 2 weeks after SNL, COX-1 immunohistochemistry was performed on the L2-S2 spinal cord. Results COX-1 immunoreactivity (COX-1-IR) was unaffected 4 h after SNL. In contrast, 4 days after SNL, the number of COX-1-IR cells increased in the ipsilateral spinal cord. COX-1-IR increased in cells with glial morphology in the superficial laminae, but decreased in the rest of the ipsilateral spinal cord 4 weeks after PSNT and 2 weeks after SNL. These changes in immunostaining were greatest at the L5 level. Conclusion These data suggest that COX-1 expression in the spinal cord is not static, but changes in a time- and laminar-dependent manner after nerve injury. These anatomic data are consistent with observations by others that spinally administered specific COX-1 inhibitors may be useful to prevent and treat neuropathic pain.

scholarly journals Biomarker Analysis of Orally Dosed, Dual Active, Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitor, AQU-118, in the Spinal Nerve Ligation (SNL) Rat Model of Neuropathic Pain

2019 ◽  
Vol 20 (4) ◽  
pp. 811 ◽  
Author(s):  
Mei Kwan ◽  
Anthony Choo ◽  
Taleen Hanania ◽  
Afshin Ghavami ◽  
Jose Beltran ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Rat Model ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Caspase 3 ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Oral Dosing ◽  
Protein Levels

There is an unmet medical need for the development of non-addicting pain therapeutics with enhanced efficacy and tolerability. The current study examined the effects of AQU-118, an orally active inhibitor of metalloproteinase-2 (MMP-2) and MMP-9, in the spinal nerve ligation (SNL) rat model of neuropathic pain. Mechanical allodynia and the levels of various biomarkers were examined within the dorsal root ganglion (DRG) before and after oral dosing with AQU-118. The rats that received the SNL surgery exhibited significant mechanical allodynia as compared to sham controls. Animals received either vehicle, positive control (gabapentin), or AQU-118. After SNL surgery, the dorsal root ganglion (DRG) of those rats dosed with vehicle had elevated messenger RNA (mRNA) expression levels for MMP-2, IL1-β & IL-6 and elevated protein levels for caspase-3 while exhibiting decreased protein levels for myelin basic protein (MBP) & active IL-β as compared to sham controls. Rats orally dosed with AQU-118 exhibited significantly reduced mechanical allodynia and decreased levels of caspase-3 in the DRG as compared to vehicle controls. Results demonstrate that oral dosing with the dual active, MMP-2/-9 inhibitor, AQU-118, attenuated mechanical allodynia while at the same time significantly reduced the levels of caspase-3 in the DRG.

scholarly journals Baicalin ameliorates neuropathic pain by suppressing HDAC1 expression in the spinal cord of spinal nerve ligation rats

2014 ◽  
Vol 113 (8) ◽  
pp. 513-520 ◽  
Author(s):  
Chen-Hwan Cherng ◽  
Kwong-Chiu Lee ◽  
Chih-Cheng Chien ◽  
Kuang-Yi Chou ◽  
Yu-Che Cheng ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation

Intrathecal CGS-26303 Pretreatment Attenuates Spinal Nerve Ligation-Induced Neuropathic Pain in the Spinal Cord

2016 ◽  
Vol 91 ◽  
pp. 532-541.e1 ◽  
Author(s):  
Hung-Chen Wang ◽  
Kuang-I. Cheng ◽  
Chao-Wen Chou ◽  
Aij-Lie Kwan ◽  
Lin-Li Chang
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation
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