p38<i>β</i>Mitogen-Activated Protein Kinase Signaling Mediates Exenatide-Stimulated Microglial<i>β</i>-Endorphin Expression

Wu, Haiyun; Mao, Xiao-Fang; Fan, Hui; Wang, Yongxiang

doi:10.1124/mol.116.107102

Cited by 34 publications

(29 citation statements)

References 76 publications

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“…It was reported that selective p38 activation inhibitor SB203580 cannot reverse neuropathic pain when given to animals after neuropathy was established72. Our recent study reported that knockdown of spinal p38α or p38β expression was not antiallodynic62. Our current results demonstrated that multiple-daily injections of siRNA/p38α or siRNA/p38β did not alter mechanical thresholds in the ipsilateral paws in neuropathic rats.…”

Section: Discussionsupporting

confidence: 47%

Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin

Wang

et al. 2017

Sci Rep

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Bulleyaconitine (BAA) has been shown to possess antinociceptive activities by stimulation of dynorphin A release from spinal microglia. This study investigated its underlying signal transduction mechanisms. The data showed that (1) BAA treatment induced phosphorylation of CREB (rather than NF-κB) and prodynorphin expression in cultured primary microglia, and antiallodynia in neuropathy, which were totally inhibited by the CREB inhibitor KG-501; (2) BAA upregulated phosphorylation of p38 (but not ERK or JNK), and the p38 inhibitor SB203580 (but not ERK or JNK inhibitor) and p38β gene silencer siRNA/p38β (but not siRNA/p38α) completely blocked BAA-induced p38 phosphorylation and/or prodynorphin expression, and antiallodynia; (3) BAA stimulated cAMP production and PKA phosphorylation, and the adenylate cyclase inhibitor DDA and PKA inhibitor H-89 entirely antagonized BAA-induced prodynorphin expression and antiallodynia; (4) The Gs-protein inhibitor NF449 completely inhibited BAA-increased cAMP level, prodynorphin expression and antiallodynia, whereas the antagonists of noradrenergic, corticotrophin-releasing factor, A1 adenosine, formyl peptide, D1/D2 dopamine, and glucagon like-peptide-1 receptors failed to block BAA-induced antiallodynia. The data indicate that BAA-induced microglial expression of prodynorphin is mediated by activation of the cAMP-PKA-p38β-CREB signaling pathway, suggesting that its possible target is a Gs-protein-coupled receptor – “aconitine receptor”, although the chemical identity is not illustrated.

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Section: Discussionsupporting

confidence: 47%

Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin

Wang

et al. 2017

Sci Rep

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“…Most of the published work so far refers to p38α and only few data is available distinguishing both isoforms, mainly because the main p38 inhibitors target both isoforms [32]. However, a recent report showed that siRNA-mediated downregulation of p38β, but not of p38α, resulted in impaired Creb1 activation in microglia [33]. These results are in good concordance with our results showing that p38α (Mapk14, Additional file 3) did not come up as positive hit in our primary screen for deactivating-microglia drug targets.…”

Section: Discussionmentioning

confidence: 99%

The atypical RhoGTPase RhoE/Rnd3 is a key molecule to acquire a neuroprotective phenotype in microglia

Neubrand

Forte-Lago

Caro

et al. 2018

J Neuroinflammation

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BackgroundOver-activated microglia play a central role during neuroinflammation, leading to neuronal cell death and neurodegeneration. Reversion of over-activated to neuroprotective microglia phenotype could regenerate a healthy CNS-supporting microglia environment. Our aim was to identify a dataset of intracellular molecules in primary microglia that play a role in the transition of microglia to a ramified, neuroprotective phenotype.MethodsWe exploited the anti-inflammatory and neuroprotective properties of conditioned medium of adipose-derived mesenchymal stem cells (CM) as a tool to generate the neuroprotective phenotype of microglia in vitro, and we set up a microscopy-based siRNA screen to identify its hits by cell morphology.ResultsWe initially assayed an array of 157 siRNAs against genes that codify proteins and factors of cytoskeleton and activation/inflammatory pathways in microglia. From them, 45 siRNAs significantly inhibited the CM-induced transition from a neurotoxic to a neuroprotective phenotype of microglia, and 50 siRNAs had the opposite effect. As a proof-of-concept, ten of these targets were validated with individual siRNAs and by downregulation of protein expression. This validation step resulted essential, because three of the potential targets were false positives. The seven validated targets were assayed in a functional screen that revealed that the atypical RhoGTPase RhoE/Rnd3 is necessary for BDNF expression and plays an essential role in controlling microglial migration.ConclusionsBesides the identification of RhoE/Rnd3 as a novel inducer of a potential neuroprotective phenotype in microglia, we propose a list of potential targets to be further confirmed with selective activators or inhibitors.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1386-z) contains supplementary material, which is available to authorized users.

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“…Furthermore, treatment with cynandione A (100 µM) stimulated the mRNA expression of IL-10 and POMC in cultured primary microglial cells. Pretreatment (30 minute earlier) with H-89 (10 µM [50]) completely hindered cynandione A-stimulated but not baseline expression of IL-10 or POMC (p < 0.05, by one-way ANOVA followed by the post-hoc Student-Newman-Keuls test; Fig. 9D, 9E).…”

Section: Cynandione a Stimulated Il-10 And β-Endorphin Expression In mentioning

confidence: 92%

“…In addition, four groups of neuropathic rats (n = 6 per group) received intrathecal injection of saline (10 µL) or the speci c PKA activation inhibitor H-89 (5 µg, dosage of which was based on the previous study [50]) 30 minutes before intrathecal injection of the vehicle (10 µL) or cynandione A (100 µg). As shown in Fig.…”

Section: Cynandione a Stimulated Il-10 And β-Endorphin Expression In mentioning

confidence: 99%

Cynandione A alleviates neuropathic pain through spinal microglial interleukin-10/β-endorphin expression following α7 nicotinic acetylcholine receptor activation

Han

Yin

Wang

et al. 2020

Preprint

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Abstract Background Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, exhibits antihypersensitivity effects in neuropathic pain. This study sought to explore the target molecule and mechanisms underlying cynandione A mechanical antiallodynia, particularly related to the spinal glial expression of IL-10/β-endorphin, cAMP/PKA/p38/CREB signaling and α7 nicotinic acetylcholine receptor (α7 nAChR) activation. Methods IL-10 and β-endorphin in the spinal cord of spinal nerve ligation-induced neuropathic pain rats and cultured primary microglia were assessed by qRT-PCR and ELISA assays. Double immunofluorescence staining of IL-10, β-endorphin with glial and neuronal cellular biomarkers was also conducted in the spinal cord and cultured primary microglia. Microglial phosphorylation of PKA, p38, CREB and STAT3 were detected using western blot. Results Cynandione A significantly attenuated mechanical allodynia in neuropathic rats and substantially increased IL-10 and β-endorphin (but not dynorphin A) expression in the spinal cords and cultured primary microglia. The IL-10 antibody attenuated cynandione A-induced spinal or microglial gene expression of β-endorphin and mechanical antiallodynia, whereas the β-endorphin antiserum blocked cynandione A-induced mechanical antiallodynia but not spinal or microglial IL-10 gene expression. The α7 nAChR antagonist methyllycaconitine significantly declined cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated microglial phosphorylation of PKA, p38 and CREB, which was inhibited by methyllycaconitine. Treatment with the adenylyl cyclase inhibitor DDA, PKA inhibitor H-89, p38 inhibitor SB203580 and CREB inhibitor KG501 attenuated cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated spinal phosphorylation of the transcription factor STAT3, which was inhibited by methyllycaconitine, H-89 and the IL-10 antibody. The STAT3 inhibitor NSC74859 weakened cynandione A-induced mechanical antiallodynia and spinal expression of β-endorphin. Conclusion Our results illustrate that cynandione A produces mechanical antiallodynia through spinal microglial expression of IL-10 via the cAMP/PKA/p38/CREB signaling and subsequent β-endorphin expression via the IL-10/STAT3 signaling, following α7 nAChR activation.

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p38βMitogen-Activated Protein Kinase Signaling Mediates Exenatide-Stimulated Microglialβ-Endorphin Expression

Cited by 34 publications

References 76 publications

Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin

Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin

The atypical RhoGTPase RhoE/Rnd3 is a key molecule to acquire a neuroprotective phenotype in microglia

Cynandione A alleviates neuropathic pain through spinal microglial interleukin-10/β-endorphin expression following α7 nicotinic acetylcholine receptor activation

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