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Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK.

Yang YJ, Hu L, Xia YP, Jiang CY, Miao C, Yang CQ, Yuan M, Wang L - J Neuroinflammation (2016)

Bottom Line: We found that resveratrol significantly attenuated trigeminal allodynia dose-dependently and decreased the increased expression of CGRP and c-Fos in the STN.Additionally, resveratrol showed an inhibitory effect on CCI-evoked astrocyte and microglia activation and reduced production of pro-inflammatory cytokines in the STN.Furthermore, the antinociceptive effect of resveratrol was partially mediated by reduced phosphorylation of MAP kinases via adenosine monophosphate-activated protein kinase (AMPK) activation.

View Article: PubMed Central - PubMed

Affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, People's Republic of China. yangyanjing@njmu.edu.cn.

ABSTRACT

Background: Glial activation and neuroinflammation in the spinal trigeminal nucleus (STN) play a pivotal role in the genesis and maintenance of trigeminal neuralgia (TN). Resveratrol, a natural compound from grape and red wine, has a potential anti-inflammatory effect. We hypothesized that resveratrol could significantly suppress neuroinflammation in the STN mediated by glial activation and further relieve TN. In this study, we evaluated whether resveratrol could alleviate trigeminal allodynia and explore the mechanism underlying the antinociceptive effect of resveratrol.

Methods: Animals were orally injected with resveratrol after chronic constriction injury (CCI) of the infraorbital nerve. Mechanical thresholds of the affected whisker pad were measured to assess nociceptive behaviors. The STN was harvested to quantify the changing levels of p-NR1, p-PKC, TNF-α, and IL1-β by western blotting and detect the expression of calcitonin gene-related peptide (CGRP) and c-Fos by immunofluorescence. Glial activation was observed by immunofluorescence and western blotting. Mitogen-activated protein kinase (MAPK) phosphorylation in vivo and in vitro was examined by western blotting.

Results: We found that resveratrol significantly attenuated trigeminal allodynia dose-dependently and decreased the increased expression of CGRP and c-Fos in the STN. Additionally, resveratrol showed an inhibitory effect on CCI-evoked astrocyte and microglia activation and reduced production of pro-inflammatory cytokines in the STN. Furthermore, the antinociceptive effect of resveratrol was partially mediated by reduced phosphorylation of MAP kinases via adenosine monophosphate-activated protein kinase (AMPK) activation.

Conclusions: AMPK activation in the STN glia via resveratrol has utility in the treatment of CCI-induced neuroinflammation and further implicates AMPK as a novel target for the attenuation of trigeminal neuralgia.

No MeSH data available.


Related in: MedlinePlus

Resveratrol regulates phosphorylation of MAPK via AMPK activation in vivo and in vitro. a Resveratrol downregulates the phosphorylation of MAPKs in vivo, including p38, ERK, and JNK; these effects were reversed by compound C. Compound C (30 μg/20 μl, i.t.) was coadministered. b Resveratrol increased p-JNK and p-ERK expression in primary astrocytes in a dose-dependent manner. c Resveratrol increased p-p38 and p-ERK expression in BV2 cells in a dose-dependent manner. Western blot bands and a data summary (n = 4 each group) are shown. *P < 0.05 and **P < 0.01 versus control; and #P < 0.05 and ##P < 0.01 versus the CCI group
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Fig6: Resveratrol regulates phosphorylation of MAPK via AMPK activation in vivo and in vitro. a Resveratrol downregulates the phosphorylation of MAPKs in vivo, including p38, ERK, and JNK; these effects were reversed by compound C. Compound C (30 μg/20 μl, i.t.) was coadministered. b Resveratrol increased p-JNK and p-ERK expression in primary astrocytes in a dose-dependent manner. c Resveratrol increased p-p38 and p-ERK expression in BV2 cells in a dose-dependent manner. Western blot bands and a data summary (n = 4 each group) are shown. *P < 0.05 and **P < 0.01 versus control; and #P < 0.05 and ##P < 0.01 versus the CCI group

Mentions: Previous studies indicated that the production of both IL-1β and TNF-α might be mediated by MAPK signaling pathways in glia [22, 23]. As shown in Fig. 6a, administration of resveratrol (400 mg/kg, p.o.) significantly reduced the levels of phosphorylated MAPKs in the STN, including p38, extracellular signal-regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK), induced by CCI. These effects were reversed by the co-administration of the AMPK inhibitor compound C (30 μg, i.t.). These results suggested that resveratrol-mediated suppression of MAPKs may be secondary to AMPK signaling activation.Fig. 5


Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK.

Yang YJ, Hu L, Xia YP, Jiang CY, Miao C, Yang CQ, Yuan M, Wang L - J Neuroinflammation (2016)

Resveratrol regulates phosphorylation of MAPK via AMPK activation in vivo and in vitro. a Resveratrol downregulates the phosphorylation of MAPKs in vivo, including p38, ERK, and JNK; these effects were reversed by compound C. Compound C (30 μg/20 μl, i.t.) was coadministered. b Resveratrol increased p-JNK and p-ERK expression in primary astrocytes in a dose-dependent manner. c Resveratrol increased p-p38 and p-ERK expression in BV2 cells in a dose-dependent manner. Western blot bands and a data summary (n = 4 each group) are shown. *P < 0.05 and **P < 0.01 versus control; and #P < 0.05 and ##P < 0.01 versus the CCI group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4837542&req=5

Fig6: Resveratrol regulates phosphorylation of MAPK via AMPK activation in vivo and in vitro. a Resveratrol downregulates the phosphorylation of MAPKs in vivo, including p38, ERK, and JNK; these effects were reversed by compound C. Compound C (30 μg/20 μl, i.t.) was coadministered. b Resveratrol increased p-JNK and p-ERK expression in primary astrocytes in a dose-dependent manner. c Resveratrol increased p-p38 and p-ERK expression in BV2 cells in a dose-dependent manner. Western blot bands and a data summary (n = 4 each group) are shown. *P < 0.05 and **P < 0.01 versus control; and #P < 0.05 and ##P < 0.01 versus the CCI group
Mentions: Previous studies indicated that the production of both IL-1β and TNF-α might be mediated by MAPK signaling pathways in glia [22, 23]. As shown in Fig. 6a, administration of resveratrol (400 mg/kg, p.o.) significantly reduced the levels of phosphorylated MAPKs in the STN, including p38, extracellular signal-regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK), induced by CCI. These effects were reversed by the co-administration of the AMPK inhibitor compound C (30 μg, i.t.). These results suggested that resveratrol-mediated suppression of MAPKs may be secondary to AMPK signaling activation.Fig. 5

Bottom Line: We found that resveratrol significantly attenuated trigeminal allodynia dose-dependently and decreased the increased expression of CGRP and c-Fos in the STN.Additionally, resveratrol showed an inhibitory effect on CCI-evoked astrocyte and microglia activation and reduced production of pro-inflammatory cytokines in the STN.Furthermore, the antinociceptive effect of resveratrol was partially mediated by reduced phosphorylation of MAP kinases via adenosine monophosphate-activated protein kinase (AMPK) activation.

View Article: PubMed Central - PubMed

Affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, People's Republic of China. yangyanjing@njmu.edu.cn.

ABSTRACT

Background: Glial activation and neuroinflammation in the spinal trigeminal nucleus (STN) play a pivotal role in the genesis and maintenance of trigeminal neuralgia (TN). Resveratrol, a natural compound from grape and red wine, has a potential anti-inflammatory effect. We hypothesized that resveratrol could significantly suppress neuroinflammation in the STN mediated by glial activation and further relieve TN. In this study, we evaluated whether resveratrol could alleviate trigeminal allodynia and explore the mechanism underlying the antinociceptive effect of resveratrol.

Methods: Animals were orally injected with resveratrol after chronic constriction injury (CCI) of the infraorbital nerve. Mechanical thresholds of the affected whisker pad were measured to assess nociceptive behaviors. The STN was harvested to quantify the changing levels of p-NR1, p-PKC, TNF-α, and IL1-β by western blotting and detect the expression of calcitonin gene-related peptide (CGRP) and c-Fos by immunofluorescence. Glial activation was observed by immunofluorescence and western blotting. Mitogen-activated protein kinase (MAPK) phosphorylation in vivo and in vitro was examined by western blotting.

Results: We found that resveratrol significantly attenuated trigeminal allodynia dose-dependently and decreased the increased expression of CGRP and c-Fos in the STN. Additionally, resveratrol showed an inhibitory effect on CCI-evoked astrocyte and microglia activation and reduced production of pro-inflammatory cytokines in the STN. Furthermore, the antinociceptive effect of resveratrol was partially mediated by reduced phosphorylation of MAP kinases via adenosine monophosphate-activated protein kinase (AMPK) activation.

Conclusions: AMPK activation in the STN glia via resveratrol has utility in the treatment of CCI-induced neuroinflammation and further implicates AMPK as a novel target for the attenuation of trigeminal neuralgia.

No MeSH data available.


Related in: MedlinePlus