PI3K/Akt Pathway: A Potential Therapeutic Target for Chronic Pain

Chen, Shuping; Zhou, Ya‐Qun; Liu, Dai-Qiang; Zhang, Wen; Manyande, Anne; Guan, Xue-Hai; Tian, Yuan; Ye, Dawei; Omar, Deeq Mohamed

doi:10.2174/1381612823666170210150147

Cited by 86 publications

(58 citation statements)

References 129 publications

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“…Although the pAKT pathway typically regulates cell growth and survival, increasing evidence indicates the involvement of this pathway in the development and maintenance of chronic pain [27,28]. Our data further showed that pAKT was predominantly expressed in DRG neurons after CFA injection.…”

Section: A and B)supporting

confidence: 72%

Intravenous administration of triptonide attenuates CFA-induced pain hypersensitivity through inhibiting AKT signaling pathway in mice

Ling

Ding

Gao

et al. 2020

Preprint

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Background: Triptonide (TPN) is a major component of Tripterygium wilfordii Hook.f., and reportedly has anti-inflammatory and neuroprotective effects. Recent studies have demonstrated that the phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays an important role in the pathogenesis of inflammatory pain. Here we investigated the anti-nociceptive effect of systemic treatment with TPN on mouse models of chronic inflammatory pain and explored possible mechanisms. Results: Unilateral hind paw injection of complete Freund’s adjuvant (CFA) induced paw edema and persistent pain hypersensitivity. Intravenous treatment with TPN attenuated CFA-induced paw edema, mechanical allodynia, and thermal hyperalgesia. Western blotting and immunofluorescence results showed that CFA induced AKT activation in the dorsal root ganglion (DRG) neurons, which was inhibited by TPN treatment. Furthermore, TPN treatment inhibited mRNA increase of proinflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), and Interleukin 6 (IL-6)] induced by CFA. Finally, pretreatment with AKT inhibitor, AKT inhibitor Ⅳ, attenuated CFA-induced mechanical allodynia and thermal hyperalgesia, and decreased the mRNA expression of pro-inflammatory cytokines. Conclusions: These data indicate that TPN attenuates CFA-induced pain potentially via inhibiting AKT-mediated pro-inflammatory cytokines production in DRG. TPN may be used for the treatment of chronic inflammatory pain.

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Section: A and B)supporting

confidence: 72%

Intravenous administration of triptonide attenuates CFA-induced pain hypersensitivity through inhibiting AKT signaling pathway in mice

Ling

Ding

Gao

et al. 2020

Preprint

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“…In animal model of DPN, PI3K/AKT pathways were repressed and then the expression of neurogenesis-related factors was downregulated [36]. Besides, activation of PI3K/AKT pathway has promise in the management of DPN, as it is capable of controlling chronic pain [37]. Other than PI3K/AKT pathway, b-catenin pathway has been mentioned to be critical in DPN.…”

Section: Discussionmentioning

confidence: 99%

Notoginsenoside R1 alleviates high glucose-evoked damage in RSC96 cells through down-regulation of miR-503

Wang

Hao

2019

Artificial Cells, Nanomedicine, and Biotechnology

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Notoginsenoside R1 (NGR1) is a major bioactive ingredient of Radix notoginseng that has promise in treating several diabetes-related diseases, like diabetic nephropathy and diabetic cardiomyopathy. This work is designed to explore if NGR1 has potential in treating diabetic peripheral neuropathy (DPN). A cell model of DPN was made by stimulating RSC96 cells with high glucose. The effects of NGR1 preconditioning were examined by conducting CCK-8 assay, flow cytometry, ROS assay and Western blot. The downstream effector and signalling of NGR1 were then explored by qRT-PCR and Western blot. High glucose incubation led to cell viability loss, apoptosis facilitation, caspase-3 and PARP cleavage, and ROS generation of RSC96 cells. Meanwhile, expression of NGF and BDNF was declined by high glucose. Preconditioning NGR1 significantly protected RSC96 cells against high glucose-evoked damage. And NGR1 prevented high glucose-induced expression of miR-503. The beneficial functions of NGR1 towards high glucose-injured RSC96 cells were impeded by miR-503 overexpression. Further, NGR1 activated PI3K/AKT and b-catenin signalling through a miR-503-dependent way. This paper illustrated the neuroprotective and neurotrophic function of NGR1 in RSC96 cells. The beneficial function may due to its regulation on miR-503 expression and the downstream signalling such as PI3K/AKT and b-catenin.

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“…Considerable research has suggested that numerous extracellular signaling molecules and intracellular transduction pathways are involved in chronic pain. 21 – 24 The Janus family tyrosine kinase (JAK)/signal transducers and activators of transcription (STAT) pathway is one of the most important cell signaling pathways in chronic pain, which includes four types of JAK and seven types of STAT. 25 , 26 Our previous study has demonstrated that STAT1 contributes to CIBP by regulating MHC II expression in spinal microglia.…”

Section: Introductionmentioning

confidence: 99%

Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models

et al. 2018

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Cancer-induced bone pain is one of the most severe types of pathological pain, which often occurs in patients with advanced prostate, breast, and lung cancer. It is of great significance to improve the therapies of cancer-induced bone pain due to the opioids’ side effects including addiction, sedation, pruritus, and vomiting. Sinomenine, a traditional Chinese medicine, showed obvious analgesic effects on a rat model of chronic inflammatory pain, but has never been proven to treat cancer-induced bone pain. In the present study, we investigated the analgesic effect of sinomenine after tumor cell implantation and specific cellular mechanisms in cancer-induced bone pain. Our results indicated that single administration of sinomenine significantly and dose-dependently alleviated mechanical allodynia in rats with cancer-induced bone pain and the effect lasted for 4 h. After tumor cell implantation, the protein levels of phosphorylated-Janus family tyrosine kinase 2 (p-JAK2), phosphorylated-signal transducers and activators of transcription 3 (p-STAT3), phosphorylated-Ca2+/calmodulin-dependent protein kinase II (p-CAMKII), and phosphorylated-cyclic adenosine monophosphate response element-binding protein (p-CREB) were persistently up-regulated in the spinal cord horn. Chronic intraperitoneal treatment with sinomenine markedly suppressed the activation of microglia and effectively inhibited the expression of JAK2/STAT3 and CAMKII/CREB signaling pathways. We are the first to reveal that up-regulation of microglial JAK2/STAT3 pathway are involved in the development and maintenance of cancer-induced bone pain. Moreover, our investigation provides the first evidence that sinomenine alleviates cancer-induced bone pain by inhibiting microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades.

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PI3K/Akt Pathway: A Potential Therapeutic Target for Chronic Pain

Cited by 86 publications

References 129 publications

Intravenous administration of triptonide attenuates CFA-induced pain hypersensitivity through inhibiting AKT signaling pathway in mice

Intravenous administration of triptonide attenuates CFA-induced pain hypersensitivity through inhibiting AKT signaling pathway in mice

Notoginsenoside R1 alleviates high glucose-evoked damage in RSC96 cells through down-regulation of miR-503

Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models

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