Kindlin-1 Regulates Astrocyte Activation and Pain Sensitivity in Rats With Neuropathic Pain

Zhao, Baisong; Pan, Yongying; Xu, Haiping

doi:10.1097/aap.0000000000000780

Cited by 11 publications

(13 citation statements)

References 26 publications

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“…Although kindlin‐1 overexpression worsened hyperalgesia in the CCI + K1 group, no significant differences were observed among the sham, sham + K1 and sham + K2 groups (Figure 1a,b; p > 0.05). Consistent with our findings in our previous study (Zhao et al, 2018), we showed that kindlin‐1 protein level was upregulated in the CCI group compared with that in the sham group and demonstrated successful overexpression and knockdown of kindlin‐1 (Figure 1c,d).…”

Section: Resultssupporting

confidence: 92%

“…However, the molecular mechanism underlying kindlin‐1‐induced NP and subsequent inflammation remains unknown. Activation of Wnt/β‐catenin signalling in astrocytes has been implicated in NP (Itokazu et al, 2014; Zhao et al, 2018). In addition, we showed increased levels of various Wnt family subtypes (e.g., Wnt3 and Wnt10) in our previous studies when kindlin‐1 level was upregulated (Zhao et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Wnt10a/β‐catenin signalling is involved in kindlin‐1‐mediated astrocyte activation in a chronic construction injury rat model

Zhao

Pan

2021

Eur J of Neuroscience

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The activation of spinal astrocytes and release of neuroinflammatory mediators are important events in neuropathic pain (NP) pathogenesis. In this study, we investigated the role of Wnt10a/β-catenin signalling in kindlin-1-mediated astrocyte activation using a chronic constriction injury (CCI) NP rat model. Using kindlin-1 overexpression and knockdown plasmids, we assessed hyperalgesia, changes in spinal astrocyte activation and the release of inflammatory mediators in a NP rat model. We also performed coimmunoprecipitation, Western blotting and real-time polymerase chain reaction (PCR) to characterize the underlying mechanisms of kindlin-1 in astrocyte cultures in vitro. Kindlin-1 was significantly upregulated in CCI rats and promoted hyperalgesia. Moreover, we observed increased kindlin-1, Wnt10a and glial fibrillary acidic protein (GFAP; biomarker for astroglial injury) levels and the release of inflammatory mediators in NP rats (p < 0.05). Inhibiting GFAP in vitro led to decreased kindlin-1 levels, prevented astrocyte activation, decreased Wnt10a level and the release of inflammatory mediators (p < 0.05). Coimmunoprecipitation showed that kindlin-1 can interact with Wnt10a. We showed that kindlin-1-mediated astrocyte activation was associated with Wnt10a/β-catenin signalling and the downstream release of inflammatory mediators in a CCI NP rat model. Our findings provide novel insights into the molecular mechanisms of kindlin-1-mediated astrocyte activation after CCI.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Wnt10a/β‐catenin signalling is involved in kindlin‐1‐mediated astrocyte activation in a chronic construction injury rat model

Zhao

Pan

2021

Eur J of Neuroscience

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“…In the rat models of neuropathy pain and cancer pain, Wnt in the spinal cord is up-regulated rapidly and permanently, activating Wnt/ β -catenin signaling in the astrocytes and elevating inflammatory cytokine levels [5]. A recent study identified kindlin-1 as a potential therapeutic target for neuropathic pain, for which Wnt-2a, Wnt-3a, Wnt-5a, and Wnt-10a may be the specific ligands [12]. Consistently, Wnt-10a, as a key target, can regulate inflammatory cytokines by regulating β -catenin downstream.…”

Section: Discussionmentioning

confidence: 99%

“…This difference is due to the different time points for observation. Microglia is significantly activated in the initial stage of chronic pain, followed by the activation of astrocytes [12]. The activated microglia participates in the maintenance of chronic pain.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Reduces Diabetic Neuropathy Pain in Rats through the Wnt 10a/β-Catenin Signaling Pathway

Zhong

Zhang

2018

BioMed Research International

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Diabetic neuropathy pain (DNP), a spontaneous pain with hyperalgesia and allodynia, greatly compromises patients' quality of life. Our previous study suggested that dexmedetomidine (DEX) can relieve hyperalgesia in rats by inhibiting inflammation and apoptosis at the level of the spinal cord. In the present study, we aimed to evaluate the role of Wnt 10a/β-catenin signaling in DEX-induced alleviation of DNP in rats. Forty-eight rats were randomly allocated to four groups (n=12/group): control, DNP, DEX, and yohimbine groups. The DNP model was established by streptozotocin (STZ) injection. The effects of DEX with or without the α2 adrenergic antagonist yohimbine were assessed by behavior tests (mechanical withdrawal threshold and thermal withdrawal latency). Spinal cord tissue was evaluated by immunofluorescence staining of astrocytes as well as for Wnt 10a and β-catenin expression, western blot analysis of Wnt 10a and β-catenin expression, and enzyme-linked immunosorbent assay measurement of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β). Rats with STZ-induced DNP had a decreased pain threshold, activated astrocytes, increased expression of Wnt 10a and β-catenin, and increased levels of proinflammatory cytokines compared to the control group, and these effects were ameliorated by treatment with DEX. Yohimbine administration partly abolished the protective effects of DEX in the DNP model rats. In conclusion, DEX alleviated DNP in rats by inhibiting inflammation and astrocyte activation, which may be attributed to downregulation of the Wnt 10a/β-catenin signaling pathway.

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“…A previous study showed that pioglitazone rapidly reduces neuropathic pain of rats in part by reducing astrocyte activation 17 . Also, Zhao et al 18 reported that silencing of Kindlin‐1 elevated the mechanical and thermal pain thresholds of rats with neuropathic pain by inhibiting activated astrocytes. Thus, inhibition of astrocyte activation can be one of the effective strategies to alleviate neuropathic pain.…”

Section: Discussionmentioning

confidence: 97%

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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Kindlin-1 Regulates Astrocyte Activation and Pain Sensitivity in Rats With Neuropathic Pain

Abstract: Kindlin-1 may regulate pain sensitivity by affecting activated astrocytes in the spinal cord. Inhibition of kindlin-1 may provide a novel paradigm for the management of neuropathic pain.

Cited by 11 publications

References 26 publications

Wnt10a/β‐catenin signalling is involved in kindlin‐1‐mediated astrocyte activation in a chronic construction injury rat model

Wnt10a/β‐catenin signalling is involved in kindlin‐1‐mediated astrocyte activation in a chronic construction injury rat model

Dexmedetomidine Reduces Diabetic Neuropathy Pain in Rats through the Wnt 10a/β-Catenin Signaling Pathway

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

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