RIP3 Inhibition ameliorates chronic constriction injury-induced neuropathic pain by suppressing JNK signaling

He, Na; Qu, Yu-Juan; Li, Danyang; Yue, Shouwei

doi:10.18632/aging.203691

Cited by 14 publications

(11 citation statements)

References 52 publications

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“…Paw withdrawal mechanical threshold (PWT). As previously reported [ 36 ], the von Frey filaments were used to determine the paw withdrawal threshold for paws in response to mechanical stimuli [ 38 ]. Briefly, rats were individually placed in a separate compartment with a metal mesh floor.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, rats were individually placed in a separate compartment with a metal mesh floor. After the rats adapted for about 30 min, von Frey filaments were vertically used to stimulate the right hind paw’s plantar surface for 3 to 5 s. Ascending order of force is used throughout the process (1 g, 1.4 g, 2 g, 4 g, 6 g, 8 g, 10 g, and 15 g), starting at 1 g and ending at 15 g [ 38 ]. Paw withdrawal, shaking, and licking were considered to be positive responses.…”

Section: Methodsmentioning

confidence: 99%

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STING Contributes to Cancer-Induced Bone Pain by Promoting M1 Polarization of Microglia in the Medial Prefrontal Cortex

Zhang

Wang

et al. 2022

Cancers

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The medial prefrontal cortex (mPFC) is the main cortical area for processing both sensory and affective aspects of pain. Recently, mPFC was reported to participate in cancer-induced bone pain (CIBP) via the mechanism of central inflammation. STING is a key component of neuroinflammation in the central neuron system by activating downstream TBK1 and NF-κB signaling pathways. We aimed to investigate whether STING regulated neuroinflammation in the mPFC in rat models of CIBP. It is worth noting that we found a significant upregulation of STING in the mPFC after CIBP, accompanied by activation of TBK1 and NF-κB signaling pathways. In addition, pain and anxiety-like behaviors were alleviated by intraperitoneal injection of the STING inhibitor C-176. Furthermore, in microglia GMI-R1 cells, C-176 reversed LPS-induced M1 polarization. Collectively, this evidence indicated that STING may contribute to cancer-induced bone pain by activating TBK1 and NF-κB, and by promoting M1 polarization of microglia in the mPFC.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

STING Contributes to Cancer-Induced Bone Pain by Promoting M1 Polarization of Microglia in the Medial Prefrontal Cortex

Zhang

Wang

et al. 2022

Cancers

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“…For instance, investigators reported that RIPK3 was highly expressed in the spinal cord, dorsal root ganglia, and hippocampus of the chronic constriction injury (CCI) model (Pu et al, 2018 ). He et al ( 2021 ) further found that RIPK3 played an important role in CCI-induced neuropathic pain, and inhibition of RIPK3 ameliorated neuropathic pain via suppressing JNK signaling. We were curious about the role of RIPK3 in neuropathic pain after SCI.…”

Section: Discussionmentioning

confidence: 99%

Receptor-Interacting Protein Kinase 3 Inhibition Relieves Mechanical Allodynia and Suppresses NLRP3 Inflammasome and NF-κB in a Rat Model of Spinal Cord Injury

Xue

Cao

Wang

et al. 2022

Front. Mol. Neurosci.

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BackgroundNeuroinflammation is critical in developing and maintaining neuropathic pain after spinal cord injury (SCI). The receptor-interacting protein kinase 3 (RIPK3) has been shown to promote inflammatory response by exerting its non-necroptotic functions. In this study, we explored the involvement of RIPK3 in neuropathic pain after SCI.MethodsThoracic (T10) SCI rat model was conducted, and the mechanical threshold in rats was measured. The expressions of RIPK3, nod-like receptor family pyrin domain-containing protein 3 (NLRP3), caspase-1, and nuclear factor-κB (NF-κB) were measured with western blotting analysis or quantitative real-time polymerase chain reaction (qRT-PCR). Double immunofluorescence staining was used to explore the colabeled NLRP3 with NeuN, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule 1 (IBA1). In addition, enzyme-linked immunosorbent assay (ELISA) was applied to analyze the levels of proinflammatory factors interleukin 1 beta (IL-1β), interleukin 18 (IL-18), and tumor necrosis factor alpha (TNF-α).ResultsThe expression of RIPK3 was elevated from postoperative days 7–21, which was consistent with the development of mechanical allodynia. Intrathecal administration of RIPK3 inhibitor GSK872 could alleviate the mechanical allodynia in SCI rats and reduce the expression levels of RIPK3. The activation of NLRP3 inflammasome and NF-κB was attenuated by GSK872 treatment. Furthermore, immunofluorescence suggested that NLRP3 had colocalization with glial cells and neurons in the L4–L6 spinal dorsal horns. In addition, GSK872 treatment reduced the production of inflammatory cytokines.ConclusionOur findings indicated that RIPK3 was an important facilitated factor for SCI-induced mechanical allodynia. RIPK3 inhibition might relieve mechanical allodynia by inhibiting NLRP3 inflammasome, NF-κB, and the associated inflammation.

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“…Sinomenine is a compound derived from the roots and stems of the cycad plant, which belongs to the Menispermaceae. Many studies have proven that sinomenine can be effective at relieving neuralgia [40][41][42] . Some reports have suggested that its mechanism of action with respect to relieving pain may be related to opioid receptors 43 .…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing and molecular docking reveal sinomenine can treat postherpetic neuralgia by regulating the expression of MMP2

Zhang

Zhao

2022

Preprint

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Objective: The pathogenesis of postherpetic neuralgia is not clear, the pain is severe, the duration is long, and the treatment effect is poor. We explored the potential mechanism of sinomenine in the treatment of postherpetic neuralgia based on single-cell sequencing and molecular docking technology and provided a theoretical basis for studying the pathogenesis of postherpetic neuralgia. Methods: Based on single-cell sequencing analysis and bioinformatics, the possible pain-causing factors of postherpetic neuralgia were identified, and the interaction between sinomenine and the target protein was analyzed using the molecular docking technique. First, the genes related to sinomenine and postherpetic neuralgia were found through various databases. Then, single-cell gene sequencing was used to identify pain-related marker genes and their role in cell subsets. The intersection of the differentially expressed (|LogFC|>1) marker gene and the postherpetic neuralgia-related genes in single-cell sequencing was used as the postherpetic neuralgia pain-causing gene set. Intersection of sinomenine and hub genes was used to identify the target genes that interact with each other, and sinomenine was molecularly docked with the target genes. Results: A total of 2524 postherpetic neuralgia-related genes and 43 sinomenine-related genes were identified through Genecard, CTD, and the GEO database. Single-cell gene sequencing was performed and revealed a total of 680 marker genes between pain and pain-free cell populations |logFC|>1. Pain-associated subpopulations were annotated mainly with microglia and astrocytes. And there were 125 intersection genes associated with postherpetic neuralgia. These genes were associated with the development of postherpetic neuralgia. 42 hub gene were identified from these crossover genes. MMP2 is the common gene of hub genes and sinomenine-related genes. Molecular docking discovers better affinity and stability between sinomenine and MMP2 protein. Conclusion: This study combined single cell analysis, bioinformatics and molecular docking to identify MMP2 as a potential target for sinomenine in the treatment of postherpetic neuralgia, which may act on microglia to alleviate pain by regulating the neuroinflammatory response and ion pathways.

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RIP3 Inhibition ameliorates chronic constriction injury-induced neuropathic pain by suppressing JNK signaling

Cited by 14 publications

References 52 publications

STING Contributes to Cancer-Induced Bone Pain by Promoting M1 Polarization of Microglia in the Medial Prefrontal Cortex

STING Contributes to Cancer-Induced Bone Pain by Promoting M1 Polarization of Microglia in the Medial Prefrontal Cortex

Receptor-Interacting Protein Kinase 3 Inhibition Relieves Mechanical Allodynia and Suppresses NLRP3 Inflammasome and NF-κB in a Rat Model of Spinal Cord Injury

Single-cell RNA sequencing and molecular docking reveal sinomenine can treat postherpetic neuralgia by regulating the expression of MMP2

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