Valproic acid mitigates spinal nerve ligation-induced neuropathic pain in rats by modulating microglial function and inhibiting neuroinflammatory response

Guo, Ao; Li, Jingfan; Luo, Li; Chen, Chun-Yi; Lu, Qing; Ke, Jianjuan; Feng, Xiaobo

doi:10.1016/j.intimp.2020.107332

Cited by 30 publications

(42 citation statements)

References 36 publications

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“…Following treatment with propofol, the aforementioned parameters were partially improved; however, the time periods still did not recover to sham‐operated rat levels ( p < .001). Meanwhile, there is abundant evidence to highlight that NP is closely associated with neuroinflammation (A. Guo et al., 2021). Therefore, we adopted ELISA to detect the expression patterns of cytokines related to neuro‐inflammation of ipsilateral dorsal root ganglitis (Figure 1c).…”

Section: Resultsmentioning

confidence: 99%

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Propofol alleviates neuropathic pain in chronic constriction injury rat models via the microRNA‐140‐3p/Jagged‐1 peptide/Notch signaling pathway

Fang

Yang

Yan

et al. 2021

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Chronic constriction injury (CCI) of the sciatic nerve was used to establish neuropathic pain (NP) models in rats. CCI rats were then treated with propofol (Pro) and their paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured. In addition, the expression patterns of tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), and IL‐10 were detected. CCI rats treated with propofol were further injected with antagomiR‐140‐3p to verify the role of miR‐140‐3p in propofol's analgesic actions. In addition to confirming the relationship between miR‐140‐3p and JAG1, the expression patterns of JAG1 itself were detected. Propofol‐treated CCI rats were also injected with Ad‐JAG1 (adenovirus‐packaged JAG1 overexpression vector and Ad‐NC) to test the role of JAG1 in propofol's analgesic mechanism of action. Finally, the levels of JAG1 and Notch pathway‐related proteins were detected Results Propofol was found to alleviate NP, including thermal hyperalgesia and mechanical pain threshold. Propofol could also ameliorate neuroinflammation by up‐regulating the expression of IL‐10 and inhibiting the release of TNF‐α and IL‐1β. Mechanically, propofol enhanced the amount of miR‐140‐3p in CCI rats via the regulation of JAG1. Down‐regulation of miR‐140‐3p, or up‐regulation of JAG1, could reduce the protective effect of propofol against NP. Propofol inhibited the activation of Notch signaling via miR‐140‐3p/JAG1 to realize its analgesic effect Conclusion Our findings indicated that propofol inhibits inflammatory responses and the Notch signaling pathway via miR‐140‐3p/JAG1 to alleviate NP. These data provide evidence to support a potential clinical therapy for NP.

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Section: Resultsmentioning

confidence: 99%

“…Meanwhile, there is abundant evidence to highlight that NP is closely associated with neuroinflammation (A. Guo et al, 2021). Therefore, we adopted ELISA to detect the expression patterns of cytokines related to neuro-inflammation of ipsilateral dorsal root ganglitis (Figure 1c).…”

Section: Protective Effect Of Propofol On Rats With Npmentioning

confidence: 99%

Propofol alleviates neuropathic pain in chronic constriction injury rat models via the microRNA‐140‐3p/Jagged‐1 peptide/Notch signaling pathway

Fang

Yang

Yan

et al. 2021

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“…Interestingly, the repeated activation of DOPr reduces the release of pro-inflammatory cytokines, such as TNF-α (Vicario et al, 2016), suggesting an impact of DOPr agonists on neuroinflammation in animal models of neuropathic pain. Along this line, an alternative approach that has been recently adopted in drug discovery in neuropathic pain is to develop new compounds able to promote the release of anti-inflammatory cytokines endowed with a neuroprotective and analgesic efficacy (Guo et al, 2021;Piotrowska, et al, 2016). Among microglial anti-inflammatory cytokines, TGF-β1 has a protective role against the development of chronic neuropathic pain by inhibiting neuroinflammation and promoting the expression of endogenous opioids within the spinal cord (Lantero et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Further studies are therefore needed, in primary cultures of microglial cells, to analyze the effects of LP2 as well as other DOPr agonists on TGF-β1 synthesis. A recent study, conducted in a neuropathic pain rat model generated through spinal nerve ligation (SNL), demonstrated that valproate mitigates SNLinduced allodynia by modulating microglial function, inhibiting neuroinflammatory response, finally promoting the expression of anti-inflammatory cytokines (TGF-β, IL-10 and IL-4) (Guo et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The Multimodal MOPr/DOPr Agonist LP2 Reduces Allodynia in Chronic Constriction Injured Rats by Rescue of TGF-β1 Signalling

et al. 2021

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Neuropathic pain is one of the most disabling forms of chronic pain and it is characterized by hyperalgesia and allodynia linked to an aberrant processing of pain transmission and to neuroinflammation. Transforming growth factor-β1 (TGF-β1) is an anti-inflammatory cytokine, which protects against neuroinflammation. It has been demonstrated that TGF-β1 and opioid receptors signalling crosstalk results in an improvement of endogenous opioid analgesia, but it is not known whether mu opioid peptide receptor (MOPr) or delta opioid peptide receptor (DOPr) agonists can positively modulate TGF-β1 pathway. In the present study, we examined the correlation between anti-allodynic effect of LP2, a dual-target MOPr/DOPr agonist, and TGF-β1 signalling in the chronic constriction injury (CCI) model. We detected a significant decrease of active TGF-β1 and of its type II receptor TGFβ-R2 levels in the spinal cord from CCI rats and a selective deficit of TGF-β1 in microglia cells both at days 11 and 21 post-ligature, as assessed by immunofluorescence analysis. LP2, when administered from the 11 days post-ligature to 21 days, was able to reduce CCI-induced mechanical allodynia by rescue of TGF-β1 and TGFβ-R2 levels. Our data suggest that the rescue of TGF-β1 signalling by dual-target MOPr/DOPr agonist LP2 could be mediated by DOPr activation in spinal microglia, thus the dual-target approach could represent a novel pharmacological approach to increase the analgesic efficacy of MOPr agonists.

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“…After treatment of propofol, the situation was partially improved, but the time still did not recover to sham-operated rats (P < 0.001). There is a research evidenced that neuropathic pain is closely associated with neuroin ammation (Guo et al 2021). Therefore, ELISA kits were used to detect the expression of cytokines related to neuroin ammation of ipsilateral dorsal root ganglitis (Fig.…”

Section: Protective Effect Of Propofol On Rats With Npmentioning

confidence: 99%

Propofol Alleviates Neuropathic Pain in CCI Rat Model via the miR-140-3p/JAG1/Notch Signaling Pathway

Fang

Yang

Yan

et al. 2021

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As a renowned anesthetic, propofol exerts excellent analgesic function in nerve injury. However, the underlying mechanism of propofol on neuropathic pain (NP) remains unknown. The research aims to analyze propofol’s analgesia mechanism to alleviate NP in CCI rats. The chronic constriction injury (CCI) of sciatic nerve was used to established NP rat models. CCI rats were treated with propofol and its paw withdrawal mechanical threshold (PMWT) and paw withdraw thermal latency (PWTL) were measured. The expressions of TNF-α, IL-1β and IL-10 were detected. CCI rats with propofol treatment were injected with antagomiR-140-3p. After the targeting relationship between miR-140-3p and JAG1 was checked, JAG1 expression was detected. Propofol-treated CCI rats were further injected with Ad-JAG1. Finally, the levels of JAG1 and Notch pathway-related proteins were detected. As a result, propofol could alleviate NP, including thermal hyperalgesia and mechanical pain threshold, and ameliorate neuroinflammation. Mechanically, propofol enhanced the level of miR-140-3p in CCI rats. JAG1 was a direct target of miR-140-3p. The downregulation of miR-140-3p or upregulation of JAG1 could reduce the protective effect of propofol against NP. Propofol inhibited activation of Notch signaling via miR-140-3p/JAG1. Overall, Propofol could inhibit the neuroinflammation and Notch signaling pathway via miR-140-3p/JAG1 to alleviate NP.

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Valproic acid mitigates spinal nerve ligation-induced neuropathic pain in rats by modulating microglial function and inhibiting neuroinflammatory response

Cited by 30 publications

References 36 publications

Propofol alleviates neuropathic pain in chronic constriction injury rat models via the microRNA‐140‐3p/Jagged‐1 peptide/Notch signaling pathway

Propofol alleviates neuropathic pain in chronic constriction injury rat models via the microRNA‐140‐3p/Jagged‐1 peptide/Notch signaling pathway

The Multimodal MOPr/DOPr Agonist LP2 Reduces Allodynia in Chronic Constriction Injured Rats by Rescue of TGF-β1 Signalling

Propofol Alleviates Neuropathic Pain in CCI Rat Model via the miR-140-3p/JAG1/Notch Signaling Pathway

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