P66shc siRNA-Encapsulated PLGA Nanoparticles Ameliorate Neuropathic Pain Following Spinal Nerve Ligation.

Nara Shin,Jaewon Beom,Hyo Jung Shin,Wonhyung Lee,Yoonyoung Yi,Dong Woon Kim,Choong-Hyun Lee

doi:10.3390/polym12051014

Abstract

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.

Highlights

Neuropathic pain, characterized by symptoms of allodynia and/or hyperalgesia, has been suggested to be a consequence of alterations in neuronal activities, immune responses, and neuroinflammatory processes [1,2]
Characterization of p66shc siRNA PLGA NPs p66shc siRNA-PLGA NPs were prepared by sonication using the W/O/W double emulsion p66shc siRNA-PLGA NPs were prepared by sonication using the W/O/W double emulsion method method to encapsulate hydrophilic siRNA
We investigated whether p66shc siRNA inhibits the mRNA expression of proinflammatory mediators in H2O2-stimulated HT22 cells

Summary

Introduction

Neuropathic pain, characterized by symptoms of allodynia and/or hyperalgesia, has been suggested to be a consequence of alterations in neuronal activities, immune responses, and neuroinflammatory processes [1,2]. In addition to mitochondrial functions and ROS, autophagy has been regarded as one of the most important mechanisms for understanding neuropathic pain. Many studies suggest that imbalance of autophagy following peripheral nerve injury leads to changes in neuronal cell functions and neurodegeneration in the spinal cord as well as the development of neuropathic pain [9,10,11,12,13]. In neuronal cells, knockdown of p66shc expression increased cell survival, whereas p66shc overexpression increased cell death involved in mitochondrial dysfunction, release of cytochrome c, and activation of the caspase cascade [19,20,21,22]

Methods

Results

Conclusion