Koumine Decreases Astrocyte-Mediated Neuroinflammation and Enhances Autophagy, Contributing to Neuropathic Pain From Chronic Constriction Injury in Rats

Jin, Gui‐Lin; Yue, Rongcai; He, Sai-di; Hong, Limian; Xu, Ying; Yu, Chang‐Xi

doi:10.3389/fphar.2018.00989

Cited by 42 publications

(56 citation statements)

References 38 publications

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“…Research studies over the past decade have suggested that proinflammatory cytokines such as Interleukin-1 beta (IL-1b) and tumor necrosis factor alpha (TNF-a) from glial cells (astrocytes and microglia) are responsible for BCP and might augment nociceptive signals in the spinal cord (Chiang et al, 2012;Lu et al, 2015). The activated glial cells release the proinflammatory cytokines that act on their receptors and express on postsynaptic neurons, leading to post-synaptic hyperexcitability and facilitatory pain transmission (Guo et al, 2007;Jin et al, 2018;Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Liquiritin Alleviates Pain Through Inhibiting CXCL1/CXCR2 Signaling Pathway in Bone Cancer Pain Rat

Xie

et al. 2020

Front. Pharmacol.

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Bone cancer pain (BCP) is an intractable clinical problem, and lacked effective drugs for treating it. Recent research showed that several chemokines in the spinal cord are involved in the pathogenesis of BCP. In this study, the antinociceptive effects of liquiritin, which is an active component extracted from Glycyrrhizae Radix, were tested and the underlying mechanisms targeting spinal dorsal horn (SDH) were investigated. The BCP group displayed a significant decrease in the mechanical withdrawal threshold on days 6, 12, and 18 when compared with sham groups. Intrathecal administration of different doses of liquiritin alleviated mechanical allodynia in BCP rats. The results of immunofluorescent staining and western blotting showed that liquiritin inhibited BCPinduced activation of astrocytes in the spinal cord. Moreover, intrathecal administration of liquiritin effectively inhibited the activation of CXCL1/CXCR2 signaling pathway and production of IL-1b and IL-17 in BCP rats. In astroglial-enriched cultures, Lipopolysaccharides (LPS) elicited the release of chemokine CXCL1, and the release was decreased in a dose-dependent manner by liquiritin. In primary neurons, liquiritin indirectly reduced the increase of CXCR2 by astroglial-enriched-conditioned medium but not directly on the CXCR2 target site. These results suggested that liquiritin effectively attenuated BCP in rats by inhibiting the activation of spinal astrocytic CXCL1 and neuronal CXCR2 pathway. These findings provided evidence regarding the the antinociceptive effect of liquiritin on BCP.

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Section: Introductionmentioning

confidence: 99%

Liquiritin Alleviates Pain Through Inhibiting CXCL1/CXCR2 Signaling Pathway in Bone Cancer Pain Rat

Xie

et al. 2020

Front. Pharmacol.

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“…Autophagy was impaired in various experimental models of neuropathic pain (NP). 12,19 Enhancement of autophagy can slow the process of NP, including TN. 10,11,20 In this study, we also explored whether the analgesic effect of Gm14461 silencing on TN was related to autophagy regulation.…”

Section: Discussionmentioning

confidence: 99%

“…It has been documented that promotion of autophagy in astrocytes can inhibit the CCI-induced activation of astrocytes and release of proinflammatory cytokines. 12 All these findings prompted us to investigate whether astrocyte activation and autophagy were involved in the analgesic mechanisms of Gm14461 silencing in TN.…”

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confidence: 99%

Silencing of lncRNA Gm14461 alleviates pain in trigeminal neuralgia through inhibiting astrocyte activation

et al. 2020

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Our previous study showed that silencing of lncRNA Gm14461 alleviated pain in a murine model of trigeminal neuralgia (TN), but the molecular mechanism remains not fully understood. Evidence indicates that astrocyte activation and autophagy are involved in the development of TN. Herein, this study aimed to elucidate whether the pain-relief effect of Gm14461 silencing in TN involved regulation of astrocyte activation and autophagy. A murine model of TN was induced by chronic constriction injury of the infraorbital nerve surgery. The mechanical withdrawal threshold (MWT) was measured to assess the analgesic effect of Gm14461 silencing. Mouse astrocytes were treated with lipopolysaccharide (LPS) as a cell model. Astrocyte activation was evaluated by glial fibrillary acidic protein (GFAP) immunofluorescence and western blot analysis of GFAP. Autophagy was evaluated by LC3 immunofluorescence and western blot analysis of autophagy-related proteins. The results showed that Gm14461 silencing increased MWT value in TN model mice. Meanwhile, Gm14461 silencing inhibited astrocyte activation and enhanced autophagy in both TN mice and LPS-treated astrocytes. The enhancement of autophagy by Gm14461 silencing involved the activation of the AMPK signaling and the suppression of the Akt/mTOR signaling. Collectively, the analgesic effect of Gm14461 silencing in TN was related to attenuation of astrocyte activation via enhancement of autophagy.

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“…Spinal cord cell apoptosis reportedly is observed during the development of neuropathic pain [17,18].…”

Section: Discussionmentioning

confidence: 99%

“…In neuropathic pain, spinal cord cells can undergo apoptosis [17,18], and apoptosis is closely related to the p38 MAPK pathway [19,20]. Therefore, we hypothesized that PKA is involved in neuropathic pain by activating the p38MAPK pathway to mediate spinal cord cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase A is involved in neuropathic pain by activating the p38MAPK pathway to mediate spinal cord cell apoptosis

Deng

Yang

Xie

et al. 2019

Preprint

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Background: Neuropathic pain is a serious clinical problem to be solved. Protein kinase A (PKA) is widely distributed in the central nervous system and participates in various signal transduction pathways to regulate cell proliferation and apoptosis. However, it is unclear whether PKA is involved in neuropathic pain. This study aimed to investigate PKA expression in neuropathic pain and its possible mechanisms of involvement. Methods: The mRNA expression dataset of neuropathic pain (GSE24982) was downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were screened using the R software. DEGs were subjected to Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. A protein-protein interaction network was constructed using the STRING database, and the Cytoscape plug-in cytoHubba was used to screen for hub genes. A spared nerve injury (SNI) rat model was established and the paw withdrawal threshold was determined using von Frey filaments. Western blotting and immunofluorescence were used to detect the expression and cellular localization of key proteins in the spinal cord, respectively. Western blotting, ELISA, and TUNEL assays were used to detect cell signal transduction, inflammation, and apoptosis, respectively. Results: Among 449 DEGs and 20 hub genes, PKA was identified as a key gene involved in neuropathic pain. After SNI, mechanical allodynia occurred, PKA expression in the spinal cord increased, the p38MAPK pathway was activated, and spinal cord inflammation and apoptosis occurred in rats. Immunofluorescence staining showed that PKA colocalized with neurons, astrocytes, and microglia, and TUNEL with GFAP, Iba-1, Neun double labeling showed that apoptotic cells were mainly neurons. Intrathecal injection of a PKA inhibitor not only relieved mechanical hyperalgesia, inflammatory reaction, and apoptosis in SNI rats, but also inhibited p38MAPK pathway activation. Intrathecal injection of a p38MAPK inhibitor attenuated mechanical hyperalgesia, inflammatory reaction, and apoptosis, but did not affect PKA expression. Conclusions: PKA is involved in neuropathic pain by activating the p38MAPK pathway to mediate spinal cord cell apoptosis. This study provides novel insights that my aid in the elucidation of the pathogenesis of neuropathic pain.

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Koumine Decreases Astrocyte-Mediated Neuroinflammation and Enhances Autophagy, Contributing to Neuropathic Pain From Chronic Constriction Injury in Rats

Cited by 42 publications

References 38 publications

Liquiritin Alleviates Pain Through Inhibiting CXCL1/CXCR2 Signaling Pathway in Bone Cancer Pain Rat

Liquiritin Alleviates Pain Through Inhibiting CXCL1/CXCR2 Signaling Pathway in Bone Cancer Pain Rat

Silencing of lncRNA Gm14461 alleviates pain in trigeminal neuralgia through inhibiting astrocyte activation

Protein kinase A is involved in neuropathic pain by activating the p38MAPK pathway to mediate spinal cord cell apoptosis

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