Effects of metformin on the expression of AMPK and STAT3 in the spinal dorsal horn of rats with neuropathic pain

Ge, Anqi; Wang, Shu; Miao, Bei; Yan, Ming

doi:10.3892/mmr.2018.8541

Cited by 26 publications

(33 citation statements)

References 48 publications

(67 reference statements)

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“…Furthermore, triclosan inhibited autophagy after si-AMPK transfection, which indicated that AMPK may be involved in triclosan-induced autophagy. Some studies have showed that AMPK activation suppresses the STAT3 signaling pathway (26,53,54); however, genetic or pharmacological inhibition of STAT3 significantly increases the ADP/ATP ratio and activates AMPK signaling (55,56). Therefore, there is a dual directional regulation mechanism between AMPK and STAT3.…”

Section: Discussionmentioning

confidence: 99%

Triclosan induces ROS‑dependent cell death and autophagy in A375 melanoma cells

et al. 2020

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Melanoma is a common type of cutaneous tumor, but current drug treatments do not satisfy clinical practice requirements. At present, mitochondrial uncoupling is an effective antitumor treatment. Triclosan, a common antimicrobial, also acts as a mitochondrial uncoupler. The aims of the present study were to investigate the effects of triclosan on melanoma cells and the underlying mechanisms. Mitochondrial membrane potential (MMP), mitochondrial morphology, mitochondrial reactive oxygen species (mito-ROS), intracellular superoxide anion and [Ca 2+ ] i were measured using confocal microscopy. It was found that triclosan application was associated with decreased A375 cell viability in a dose-and time-dependent manner and these effects may have cell specificity. Furthermore, triclosan induced MMP depolarization, ATP content decrease, mito-ROS and [Ca 2+ ] i level increases, excessive mitochondrial fission, AMP-activated protein kinase (AMPK) activation and STAT3 inhibition. Moreover, these aforementioned effects were reversed by acetylcysteine treatment. Triclosan acute treatment also induced mitochondrial swelling, which was reversed after AMPK-knockdown associated with [Ca 2+ ] i overload. Cell death was caused by STAT3 inhibition but not AMPK activation. Moreover, triclosan induced autophagy via the ROS/AMPK/p62/microtubule-associated protein 1A/1B-light chain 3 (LC3) signaling pathway, which may serve a role in feedback protection. Collectively, the present results suggested that triclosan increased mito-ROS production in melanoma cells, following induced cell death via the STAT3/Bcl-2 pathway and autophagy via the AMPK/p62/LC3 pathway.

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Section: Discussionmentioning

confidence: 99%

Triclosan induces ROS‑dependent cell death and autophagy in A375 melanoma cells

et al. 2020

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“…Among these protein kinase and transcription factors, the role of AMPK in spinal cord glial activation has been received attention in recent years. In CCI rats, phosphorylated-AMPK was expressed at lower levels in the dorsal spinal cord [64]. Moreover, activation of AMPK can effectively inhibit the activation of spinal microglia and astrocytes, which result in pain relief [64].…”

Section: Discussionmentioning

confidence: 99%

“…In CCI rats, phosphorylated-AMPK was expressed at lower levels in the dorsal spinal cord [64]. Moreover, activation of AMPK can effectively inhibit the activation of spinal microglia and astrocytes, which result in pain relief [64]. Lidocaine suppressed morphine-induced activation of spinal cord microglia and downregulated inflammatory cytokines production by activating AMPK [65].…”

Section: Discussionmentioning

confidence: 99%

CB2/miR-124 signaling down-regulate the expression of purinergic P2X4 and P2X7 receptor in dorsal spinal cord of CCI rats

Xu¹,

Yang²,

Li³

et al. 2020

Preprint

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Background: The importance of P2X purinoceptors, CB2 receptor and microRNA-124(miR-124) in spinal cord microglia to the development of neuropathic pain was demonstrated in numerous previous studies. The upregulation of P2X4 and P2X7 receptors in spinal dorsal horn microglia is involved in the development of pain behavior caused by peripheral nerve injury. However, it is not clear whether the expression of P2X4 and P2X7 receptors at dorsal spinal cord will be influenced by CB2 receptor or miR-124 in rats after chronic sciatic nerve injury.Methods: Chronic constriction injury (CCI) of the sciatic nerve was performed in rats to induce neuropathic pain. Tests of the mechanical withdrawal threshold (MWT) were carried out to assess the response of the paw to mechanical stimulus. The expression of miR-124, P2X4, P2X7 and CB2 receptor were detected with RT-PCR. The protein expression of P2X4, P2X7 and CB2 receptor, RhoA, ROCK1, ROCK2, p-p38MAPK and p-NF-kappaBp65 was detected with Western blotting analysis. Results: Intrathecal administration of CB2 receptor agonist AM1241 significantly attenuated CCI-induced mechanical allodynia and significantly inhibited the increased expression of P2X4 and P2X7 receptors at the mRNA and protein levels, which imply that P2X4 and P2X7 receptors expression are down-regulated by AM1241 in CCI rats. Western blot analysis showed that AM1241 suppressed the elevated expression of RhoA, ROCK1, ROCK2, p-p38MAPK and NF-κBp65 in the dorsal spinal cord induced by CCI. After administration with Y-27632 (ROCK inhibitor), SB203580 (P38MAPK inhibitor) or PDTC (NF-κB inhibitor), the levels of P2X4 and P2X7 receptors expression in the dorsal spinal cord were lower than those in CCI rats, which imply that the ROCK/P38MAPK pathway and NF-κB activation may contribute to the increased expression of P2X4 and P2X7 receptor. On the other hand, in CCI rats, AM1241 treatment evoked the increased expression of CB2 receptor and miRNA-124, which can be inhibited by intrathecal injection of CB2 receptor antagonist AM630, which indicate that the increased expression of miRNA-124 may be medicated by CB2 receptor activation. In addition, the increased expression of P2X4 and P2X7 receptors in the dorsal spinal cord of CCI rats were inhibited by miRNA-124 agomir. Furthermore, intrathecal injection of miRNA-124 agomir could efficiently inhibit the ROCK/P38MAPK pathway and NF-κB activation in CCI rats. Moreover, AM1241 treatment significantly inhibited the expression of P2X4 and P2X7 receptors, and this suppression is enhanced by pretreatment with miRNA-124 agomir. On the contrast, the inhibitory effect of AM1241 on the expression of P2X4 and P2X7 receptor can be reversed by pretreatment with miRNA-124 antagomir.Conclusions: In CCI rats, intrathecal injection of AM1241 could efficiently induce the increased expression of miRNA-124, while inhibiting the ROCK/P38MAPK pathway and NF-κB activation in dorsal spinal cord. CB2 receptor/miRNA-124 signaling induced the decreased P2X4 and P2X7 receptors expression via inhibit the ROCK/P38MAPK pathway and NF-κB activation.

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“…Several signal molecules such as JNK, AMPKα1, and mTOR proteins are known to play important roles in the regulation of pain or antinociception [32][33][34]. However, the relationship of the expression of JNK, AMPKα1 and mTOR proteins and acute stress-induced antinociception in the spinal cord has not been reported.…”

Section: Discussionmentioning

confidence: 99%

The Molecular Signatures of Acute-immobilization-induced Antinociception and Chronic-immobilization-induced Antinociceptive Tolerance

2019

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In the present study, the productions of antinociception induced by acute and chronic immobilization stress were compared in several animal pain models. In the acute immobilization stress model (up to 1 hr immobilization), the antinociception was produced in writhing, tail-flick, and formalin-induced pain models. In chronic immobilization stress experiment, the mouse was enforced into immobilization for 1 hr/day for 3, 7, or 14 days, then analgesic tests were performed. The antinociceptive effect was gradually reduced after 3, 7 and 14 days of immobilization stress. To delineate the molecular mechanism involved in the antinociceptive tolerance development in the chronic stress model, the expressions of some signal molecules in dorsal root ganglia (DRG), spinal cord, hippocampus, and the hypothalamus were observed in acute and chronic immobilization models. The COX-2 in DRG, p-JNK, p-AMPKα1, and p-mTOR in the spinal cord, p-P38 in the hippocampus, and p-AMPKα1 in the hypothalamus were elevated in acute immobilization stress, but were reduced gradually after 3, 7 and 14 days of immobilization stress. Our results suggest that the chronic immobilization stress causes development of tolerance to the antinociception induced by acute immobilization stress. In addition, the COX-2 in DRG, p-JNK, p-AMPKα1, and p-mTOR in the spinal cord, p-P38 in the hippocampus, and p-AMPKα1 in the hypothalamus may play important roles in the regulation of antinociception induced by acute immobilization stress and the tolerance development induced by chronic immobilization stress.

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Effects of metformin on the expression of AMPK and STAT3 in the spinal dorsal horn of rats with neuropathic pain

Cited by 26 publications

References 48 publications

Triclosan induces ROS‑dependent cell death and autophagy in A375 melanoma cells

Triclosan induces ROS‑dependent cell death and autophagy in A375 melanoma cells

CB2/miR-124 signaling down-regulate the expression of purinergic P2X4 and P2X7 receptor in dorsal spinal cord of CCI rats

The Molecular Signatures of Acute-immobilization-induced Antinociception and Chronic-immobilization-induced Antinociceptive Tolerance

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