Contributions of p38 and ERK to the antinociceptive effects of TGF-β1 in chronic constriction injury-induced neuropathic rats

Chen, Nan‐Fu; Chen, Wu-Fu; Sung, Chun-Sung; Lu, Ching-Hsiang; Chen, Chunlin; Hung, Han-Chun; Feng, Chien-Wei; Chen, Chunhong; Tsui, Kuan‐Hao; Kuo, Hsi-Kung; Wang, Hui‐Min David; Wen, Zhi‐Hong; Huang, Sheng-Lung

doi:10.1186/s10194-016-0665-2

Cited by 37 publications

(34 citation statements)

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“…Additionally, PKM2 increased strongly in LPS-activated macrophages, translocated into the nucleus and bounded with HIF-1α and STAT3 to promote the expression of inflammatory cytokines Il-1β and TNF-α [ 31 , 46 ]. Inhibiting these signaling pathways can effectively suppress the generation of pro-inflammatory and neuropathic pain [ 28 – 30 ]. Accordingly, we examined the phosphorylation of these signaling pathways after intrathecal injection of PKM2 siRNA.…”

Section: Discussionmentioning

confidence: 99%

“…PKM2 can phosphorylates ERK1/2, STAT-3 and PI3K/AKT, enhancing cell proliferation and subsequent related gene transcription [ 25 – 27 ]. These signaling pathways are activated in spinal cord (SC) after nerve injury and contribute to the development of neuropathic pain [ 28 – 30 ]. PKM2 also interacts with hypoxia-inducible factor 1-alpha(HIF-1α) and upregulates the expression of IL-1β [ 31 ] in LPS-activated macrophages.…”

Section: Introductionmentioning

confidence: 99%

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PKM2 is involved in neuropathic pain by regulating ERK and STAT3 activation in rat spinal cord

et al. 2018

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BackgroundPyruvate kinase isozymes M2 (PKM2), as a member of pyruvate kinase family, plays a role of glycolytic enzyme in glucose metabolism. It also functions as protein kinase in cell proliferation, signaling, immunity, and gene transcription. In this study, the role of PKM2 in neuropathic pain induced by chronic constriction injury (CCI) was investigated.MethodsRats were randomly grouped to establish CCI models. PKM2, extracellular regulated protein kinases (EKR), p-ERK, signal transducers and activators of transcription (STAT3), p-STAT3, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and p-PI3K/AKT proteins expression in spinal cord was examined by Western blot analysis. Cellular location of PKM2 was examined by immunofluorescence. Knockdown of PKM2 was achieved by intrathecal injection of specific small interfering RNA (siRNA). Von Frey filaments and radiant heat tests were performed to determine mechanical allodynia and thermal hyperalgesia respectively. Lactate and adenosine triphosphate (ATP) contents were measured by specific kits. Tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels were detected by ELISA kits.ResultsCCI markedly increased PKM2 level in rat spinal cord. Double immunofluorescent staining showed that PKM2 co-localized with neuron, astrocyte, and microglia. Intrathecal injection of PKM2 siRNA not only attenuated CCI-induced ERK and STAT3 activation, but also attenuated mechanical allodynia and thermal hyperalgesia induced by CCI. However, PKM2 siRNA failed to inhibit the activation of AKT. In addition, PKM2 siRNA significantly suppressed the production of lactate and pro-inflammatory mediators.ConclusionOur findings demonstrate that inhibiting PKM2 expression effectively attenuates CCI-induced neuropathic pain and inflammatory responses in rats, possibly through regulating ERK and STAT3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PKM2 is involved in neuropathic pain by regulating ERK and STAT3 activation in rat spinal cord

et al. 2018

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“…By following Ras-Raf-MEK-ERK, ERK plays a key role in signal transduction from cell membrane receptors to the nucleus. This shows that activation of ERK in the spinal cord dorsal horn neurons is significant in producing and maintaining central sensitization[ 24 ]. This indicates that the ERK pathway is involved in regulation of nociceptive signals in the spinal cord, and early intervention at the spinal cord level should be effective in blocking pain transmission[ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Moxibustion eases chronic inflammatory visceral pain through regulating MEK, ERK and CREB in rats

Li¹,

Huang²,

Yang³

et al. 2017

WJG

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AIMTo investigate the effects of herb-partitioned moxibustion (HPM) on phosphorylation of mitogen-activated extracellular signal-regulated kinase (MEK)1, extracellular signal-regulated kinase (ERK)1/2 and cAMP response element binding protein (CREB) in spinal cord of rats with chronic inflammatory visceral pain (CIVP), and to explore the central mechanism of HPM in treating CIVP.METHODSMale Sprague-Dawley rats were randomized into normal, model, HPM, sham-HPM, MEK-inhibitor and dimethyl sulfoxide (DMSO) groups. The CIVP model was established using an enema mixture of trinitrobenzene sulfonic acid and ethanol. HPM was applied at bilateral Tianshu (ST25) and Qihai (CV6) acupoints in the HPM group, while in the sham-HPM group, moxa cones and herb cakes were only placed on the same points but not ignited. The MEK-inhibitor and DMSO groups received L5-L6 intrathecal injection of U0126 and 30% DMSO, respectively. Abdominal withdrawal reflex (AWR), mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were applied for the assessment of pain behavior. The colonic tissue was observed under an optical microscope after hematoxylin-eosin staining. Expression of phosphor (p)MEK1, pERK1/2 and pCREB in rat spinal cord was detected using Western blotting. The levels of MEK, ERK and CREB mRNA in rat spinal cord were detected using real-time polymerase chain reaction.RESULTSCompared with the normal group, the AWR scores were increased significantly (P < 0.01) and the MWT and TWL scores were decreased significantly (P < 0.05) in the model, sham-HPM and DMSO groups. Compared with the model group, the AWR scores were decreased significantly (P < 0.01) and the MWT and TWL scores were increased significantly in the HPM and MEK-inhibitor groups (P < 0.05). Compared with the sham-HPM and DMSO groups, the AWR scores were decreased significantly (P < 0.01) and the MWT and TWL scores were increased significantly (P < 0.05) in the HPM and MEK-inhibitor groups. Compared with the normal group, the expression of pMEK1, pERK1/2 and pCREB proteins and the levels of MEK, ERK and CREB mRNA in rat spinal cord were increased significantly in the model, sham-HPM and DMSO groups (P < 0.01 or < 0.05). Compared with the model group, the expression of pMEK1, pERK1/2 and pCREB proteins and the levels of MEK, ERK and CREB mRNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups (P < 0.01 or < 0.05). Compared with the sham-HPM and DMSO groups, expression of pMEK1, pERK1/2 and pCREB proteins and the levels of MEK, ERK and CREB mRNA in rat spinal cord were reduced significantly in the HPM and MEK-inhibitor groups (P < 0.01 or < 0.05).CONCLUSIONHPM down-regulates protein phosphorylation of MEK1, ERK1/2 and CREB, and mRNA expression of MEK, ERK and CREB, inhibiting activation of the MEK/ERK/CREB signaling pathway in the spinal cord of CIVP rats, which is possibly a critical central mechanism of the analgesic effect of HPM.

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“…(Bottner et al, 2000) In preclinical studies, TGF-β1 prevented the development of neuropathic pain associated with traumatic nerve injury and reversed previously established neuropathic pain. (Chen et al, 2016;Chen et al, 2013;Echeverry et al, 2009).…”

Section: Perturbed Neuroinflammation-related Pathways Associated Withmentioning

confidence: 99%

Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors

Miaskowski

Topp

Conley

et al. 2019

Journal of Neuroimmunology

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A B S T R A C TPaclitaxel is a common chemotherapy drug associated with the development of chronic paclitaxel-induced peripheral neuropathy (PIPN). PIPN is associated with neuroinflammatory mechanisms in pre-clinical studies. Here, we evaluated for differential gene expression (DGE) in peripheral blood between breast cancer survivors with and without PIPN and for neuroinflammatory (NI) related signaling pathways and whole-transcriptome profiles from other experiments. Pathway impact analysis identified 8 perturbed NI related pathways. Expression profile analysis found 15 experiments having similar whole-transcriptome profiles of DGE related to neuroinflammation and PIPN. These findings suggest that perturbations in pathways associated with neuroinflammation are found in cancer survivors with PIPN.

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Contributions of p38 and ERK to the antinociceptive effects of TGF-β1 in chronic constriction injury-induced neuropathic rats

Cited by 37 publications

References 53 publications

PKM2 is involved in neuropathic pain by regulating ERK and STAT3 activation in rat spinal cord

PKM2 is involved in neuropathic pain by regulating ERK and STAT3 activation in rat spinal cord

Moxibustion eases chronic inflammatory visceral pain through regulating MEK, ERK and CREB in rats

Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors

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