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    Erythropoietin reduces nerve demyelination, neuropathic pain behavior and microglial MAPKs activation through erythropoietin receptors on Schwann cells in a rat model of peripheral neuropathy. Huang Chun-Ta,Chen Seu-Hwa,Lin Shih-Chang,Chen Wei-Ting,Lue June-Horng,Tsai Yi-Ju Glia Neuroprotective effects of erythropoietin (EPO) on peripheral nerve injury remain uncertain. This study investigated the efficacy of EPO in attenuating median nerve chronic constriction injury (CCI)-induced neuropathy. Animals received an intraneural injection of EPO at doses of 1,000, 3,000, or 5,000 units/kg 15 min before median nerve CCI. Afterwards, the behavioral and electrophysiological tests were conducted. Immunohistochemistry and immunoblotting were used for qualitative and quantitative analysis of microglial and mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, activation. Enzyme-linked immunosorbent assay and microdialysis were applied to measure pro-inflammatory cytokine and glutamate responses, respectively. EPO pre-treatment dose-dependently ameliorated neuropathic pain behavior, decreased microglial and MAPKs activation, and diminished the release of pro-inflammatory cytokines and glutamate in the ipsilateral cuneate nucleus after CCI. Moreover, EPO pre-treatment preserved myelination of the injured median nerve on morphological investigation and suppressed injury-induced discharges. We also observed that EPO receptor (EPOR) expression was up-regulated in the injured nerve after CCI. Double immunofluorescence showed that EPOR was localized to Schwann cells. Furthermore, siRNA-mediated knockdown of EPOR expression eliminated the therapeutic effects of EPO on attenuating the microglial and MAPKs activation, pro-inflammatory cytokine responses, injury discharges, and neuropathic pain behavior in CCI rats. In conclusion, binding of EPO to its receptors on Schwann cells maintains myelin integrity and blocks ectopic discharges in the injured median nerve, that in the end contribute to attenuation of neuropathic pain via reducing glutamate release from primary afferents and inhibiting activation of microglial MAPKs and production of pro-inflammatory cytokines. 10.1002/glia.23461
    Pain behavior and nerve electrophysiology in the CCI model of neuropathic pain. Gabay Eran,Tal Michael Pain Experimental painful peripheral neuropathy induced by chronic constriction injury (CCI) of the sciatic nerve results in cutaneous thermal and mechanical allodynia of the hind limb. Our histological studies indicate that the major pathology in the CCI model is a loss of large diameter myelinated fibers distal to the site of injury. Electrophysiological recordings from axons central to the lesion that respond to electrical stimulation distal to it, revealed severe fiber loss, reflected by a decrease (P < 0.05) from 5.2+/-6.8 to 0.5+/-0.1 axons/microfilament 5-9 days post operatively (dpo). At 12-15th dpo some recovery was seen, i.e. 1.5+/-0.28 axons/microfilament in the CCI group. The ratio of A- to C-axons in the control group remained constant throughout the experiment. A distinct area in the paw served by the injured nerve was selected to study the response of axons in each microfilament to mechanical stimulation with von Frey monofilaments. In the control group, 91%+/-0.6 of the microfilaments had at least one axon with a receptive field in this area. This decreased to 17%+/-2.9 in the CCI group 5-9 dpo, but had partially recovered to 44+/-4.2% by 12-15-dpo. Our conclusion is that in the CCI model there is an equal reduction in the number of A and C axons conducting past the lesion site, thus preserving a constant ratio between the two fiber populations. This is true despite the apparent preservation of C-fibers observed in previous histological studies. 10.1016/j.pain.2004.04.021
    SETD7 mediates spinal microgliosis and neuropathic pain in a rat model of peripheral nerve injury. Shen Yu,Ding Zhuofeng,Ma Shengyun,Ding Zijin,Zhang Yu,Zou Yu,Xu Fangting,Yang Xin,Schäfer Michael K E,Guo Qulian,Huang Changsheng Brain, behavior, and immunity Gene transcription regulation is critical for the development of spinal microgliosis and neuropathic pain after peripheral nerve injury. Using a model of chronic constriction injury (CCI) of the sciatic nerve, this study characterized the role of SET domain containing lysine methyltransferase 7 (SETD7) which monomethylates histone H3 lysine 4 (H3K4me1), a marker for active gene transcription. SETD7 protein expression in the spinal dorsal horn ipsilateral to nerve lesion was increased from one day to 14 days after CCI, concomitantly with the expression of inflammatory genes, Ccl2, Il-6 and Il-1β. The CCI-induced SETD7 expression was predominantly localized to microglia, as demonstrated by immunohistochemistry and western blot from magnetic activated cell sorted spinal microglia. SETD7 knockdown by intrathecal lentivirus shRNA delivery prior to CCI prevented spinal microgliosis and neuropathic pain, whereas lentiviral SETD7 transduction exacerbated these symptoms. In addition, SETD7 regulated H3K4me1 level and expression of inflammatory mediators both in CCI rats and in the HAPI rat microglia cell line. Accordingly, PFI-2, a specific inhibitor of SETD7 monomethylation activity, suppressed the lipopolysaccharides-induced amoeboid morphology of primary microglia and the expression of inflammatory genes, Ccl2, Il-6 and Il-1β. Moreover, intrathecal administration of PFI-2 alleviated CCI-induced neuropathic pain. However, this effect was observed in male but not in female rats. These results demonstrate a critical role of SETD7 in the development of spinal microgliosis and neuropathic pain subsequently to peripheral nerve injury. The pharmacological approach further suggests that SETD7 is a new target for the treatment of neuropathic pain. The underlying mechanisms may involve H3K4me1-dependent regulation of inflammatory gene expression in microglia. 10.1016/j.bbi.2019.09.007
    Inhibition of cytochrome P450c17 reduces spinal astrocyte activation in a mouse model of neuropathic pain via regulation of p38 MAPK phosphorylation. Choi Sheu-Ran,Beitz Alvin J,Lee Jang-Hern Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie We have recently demonstrated that the neurosteroid-metabolizing enzyme, cytochrome P450c17 is increased in spinal astrocytes contributing to the development of mechanical allodynia in chronic constriction injury (CCI)-induced neuropathic mice. However, the mechanisms by which spinal P450c17 modulates pathological changes in astrocytes remain unclear. In this study we investigated whether P450c17 modulates astrocyte activation and whether this process is mediated by spinal p38 mitogen-activated protein kinase phosphorylation ultimately leading to the development of mechanical allodynia in CCI mice. Sciatic nerve injury induced a significant increase in glial fibrillary acidic protein (GFAP) expression in the superficial dorsal horn (SDH, laminae I-II) and nucleus proprius (NP, laminae III-IV) regions of the spinal cord dorsal horn. Repeated daily (from days 0-3 post-surgery) intrathecal administration of the P450c17 inhibitor, ketoconazole (10 nmol) significantly inhibited the CCI-induced increase in GFAP-immunoreactivity, but had no effect on the CCI-induced increase in Iba-1-immunoreactivity. In addition, intrathecal administration of ketoconazole significantly inhibited the CCI-induced increase in p38 phosphorylation, while the levels of ERK and JNK phosphorylation remained unchanged. The CCI-induced development of mechanical allodynia was attenuated by administration of either ketoconazole (10 nmol) or the p38 MAPK inhibitor, SB203580 (5 nmol). Administration of a sub-effective dose of SB203580 (0.5 nmol) potentiated the pharmacological effect of ketoconazole (1 nmol) on spinal GFAP-immunostaining, as well as, the development of mechanical allodynia following CCI. Collectively these data suggest that spinal P450c17 activates astrocytes via p38 phosphorylation, ultimately leading to the development of mechanical allodynia in a model of peripheral neuropathy. 10.1016/j.biopha.2019.109299
    Sphingosine-1-phosphate receptor 2 modulates pain sensitivity by suppressing the ROS-RUNX3 pathway in a rat model of neuropathy. Li Yinyu,Li Huanli,Han Jinsong Journal of cellular physiology Neuropathic pain correlates with a lesion or other dysfunction in the nervous system. Sphingosine-1-phosphate receptor 2 (S1P2) is expressed in the central nervous system and modulates synaptic plasticity. The present study aimed to investigate the role of S1P2 in neuropathic pain caused by chronic constriction injury (CCI). Sprague-Dawley rats were allocated into eight groups (n = 15 for each group): sham, CCI, CCI + green fluorescent protein, CCI + S1P2, CCI + Ctrl-short hairpin RNA (shRNA), CCI + S1P2 shRNA, CCI + S1P2 + CYM-5442, and CCI + S1P2 shRNA + CYM-5442. The CCI model was established via sciatic nerve ligation. S1P2 was overexpressed or knocked down by intrathecal injection of adeno-associated virus-S1P2 (AAV-S1P2) or AAV-S1P2 shRNA. The S1P1 agonist, CYM-5442 (1 mg/kg), was injected intraperitoneally after surgery. S1P2 expression, pain thresholds, apoptosis signaling, inflammation, and oxidative stress in rats were then examined. We found that sciatic nerve injury downregulated S1P2 expression in the spinal cords of rats. S1P2 overexpression enhanced pain thresholds. In contrast, S1P2 knockdown decreased pain thresholds in rats exposed to CCI. CCI and S1P2 silencing increased secretion of interleukin-1β (IL-1β), IL-6, and CCL2, whereas S1P2 overexpression decreased. S1P2 impeded CCI-induced reactive oxygen species (ROS) production and runt-related transcription factors 3 (RUNX3) downregulation, and S1P2 knockdown had the opposite effect. S1P2 overexpression suppressed Bax and active caspase 3 expression and promoted Bcl-2 expression, whereas loss of S1P2 reversed their expression. Additionally, S1P1 activation counteracted the effect of S1P2 on pain sensitivity. In conclusion, S1P2 is downregulated in CCI rats and may help modulate neuropathic pain via the ROS/RUNX3 pathway. 10.1002/jcp.29280
    Effects of miR-26a-5p on neuropathic pain development by targeting MAPK6 in in CCI rat models. Zhang Yang,Su Zhen,Liu Hai-Lin,Li Lin,Wei Meng,Ge Dong-Jian,Zhang Zhi-Jie Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie MicroRNA are emerging as significant regulators of neuropathic pain progression. In addition, neuroinflammation contributes a lot to neuropathic pain. miR-26a-5p has been identified as an inflammation-associated miRNA in multiple pathological processes. However, little is known about the biological role of miR-26a-5p in neuroinflammation and neuropathic pain development. Therefore, we aimed to investigate the function of miR-26a-5p in neuropathic pain by establishing a rat model using chronic sciatic nerve injury (CCI). A significant decrease of miR-26a-5p expression was observed in the spinal cord tissues form the CCI rats compared to the control group. Moreover, overexpression of miR-26a-5p significantly repressed neuropathic pain and neuroinflammation in CCI rats. MAPK6 was identified as a direct downstream target gene of miR-26a-5p and confirmed by dual-luciferase reporter assays. As displayed, overexpression of miR-26a-5p greatly reduced MAPK6 levels in vitro and in vivo. Meanwhile, MAPK6 expression and miR-26a-5p were oppositely correlated in CCI rats. Furthermore, up-regulation of MAPK6 obviously reversed the suppressive effect of miR-26a-5p on neuroinflammation and neuropathic pain progression. Taken these together, our results implied that miR-26a-5p could act as a negative regulator of neuropathic pain development through targeting MAPK6, which indicated that miR-26a-5p might serve as a potential therapeutic target for neuropathic pain. 10.1016/j.biopha.2018.08.005
    CRNDE enhances neuropathic pain via modulating miR-136/IL6R axis in CCI rat models. Zhang Dawei,Mou Jun-Ying,Wang Fang,Liu Juan,Hu Xue Journal of cellular physiology Neuropathic pain has been reported as a type of chronic pain due to the primary dysfunction of the somatosensory nervous system. It is the most serious types of chronic pain, which can lead to a significant public health burden. But, the understanding of the cellular and molecular pathogenesis of neuropathic pain is barely complete. Long noncoding RNAs (lncRNAs) have recently been regarded as modulators of neuronal functions. Growing studies have indicated lncRNAs can exert crucial roles in the development of neuropathic pain. Therefore, our present study focused on the potential role of the lncRNA Colorectal Neoplasia Differentially Expressed (CRNDE) in neuropathic pain progression. Firstly, a chronic constrictive injury (CCI) rat model was built. CRNDE was obviously increased in CCI rats. Interestingly, overexpression of CRNDE enhanced neuropathic pain behaviors. Neuroinflammation was induced by CRNDE and as demonstrated, interleukin-10 (IL-10), IL-1, IL-6, and tumor necrosis factor-α (TNF-α) protein levels in CCI rats were activated by LV-CRNDE. For another, miR-136 was obviously reduced in CCI rats. Previously, it is indicated that miR-136 participates in the spinal cord injury via an inflammation in a rat model. Here, firstly, we verified miR-136 could serve as CRNDE target. Loss of miR-136 triggered neuropathic pain remarkably via the neuroinflammation activation. Additionally, IL6R was indicated as a target of miR-136 and miR-136 regulated its expression. Subsequently, we confirmed that CRNDE could induce interleukin 6 receptor (IL6R) expression positively. Overall, it was implied that CRNDE promoted neuropathic pain progression via modulating miR-136/IL6R axis in CCI rat models. 10.1002/jcp.28790