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Scutellarin Exerts Anti-Inflammatory Effects in Activated Microglia/Brain Macrophage in Cerebral Ischemia and in Activated BV-2 Microglia Through Regulation of MAPKs Signaling Pathway

  • Hao-Lun Chen
  • Wen-Ji Jia
  • Hong-E Li
  • Hong Han
  • Fan Li
  • Xiao-Li-Na Zhang
  • Juan-Juan Li
  • Yun YuanEmail author
  • Chun-Yun WuEmail author
Original Paper
  • 38 Downloads

Abstract

Background

Scutellarin, an herbal compound, can effectively suppress the inflammatory response in activated microglia/brain macrophage(AM/BM) in experimentally induced cerebral ischemia; however, the underlying mechanism for this has not been fully clarified. We sought to elucidate if scutellarin would exert its anti-inflammatory effects on AM/BM through the MAPKs pathway.

Materials and Methods

Western blot and immunofluorescence labeling were used to determine the expression of the MAPKs pathway in AM/BM in rats subjected to middle cerebral artery occlusion (MCAO) also in lipopolysaccharide (LPS)-activated BV-2 microglia in vitro. Furthermore, expression of p-p38 along with that of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta(IL-1β), and inducible nitric oxide synthase (iNOS) in LPS-activated microglia subjected to pretreatment with p38 inhibitor SB203580, p38 activator sc-201214, scutellarin, or a combination of them was evaluated.

Findings

Scutellarin markedly attenuated the expression of p-p38, p-JNK in AM/BM in MCAO rats and in vitro. Conversely, p-ERK1/2 expression level was significantly increased by scutellarin. Meanwhile, scutellarin suppressed the expression of proinflammatory mediators including iNOS, TNF-α, and IL-1β in AM/BM. More importantly, SB203580 suppressed p-p38 protein expression level in LPS-activated BV-2 microglia that was coupled with decreased expression of proinflammatory mediators (TNF-α, iNOS) in LPS-activated BV-2 microglia. However, p38 activator sc-201214 increased expression of proinflammatory mediators TNF-α, iNOS, and IL-1β. Interestingly, the decreased expression of both proinflammatory markers by p38 MAPK inhibitor and increased expression of proinflammatory markers by p38 MAPK activator were compatible with that in BV-2-activated microglia pretreated with scutellarin.

Conclusions

The results suggest that scutellarin down-regulates the expression of proinflammatory mediators in AM/BM through suppressing the p-JNK and p-p38 MAPKs. Of note, the anti-inflammatory effect of p38 MAPK inhibitor and scutellarin is comparable. Besides, p38 MAPKs activator reverses the effect of scutellarin. Additionally, scutellarin increases p-ERK1/2 expression that may be neuroprotective.

Keywords

Scutellarin Activated microglia/brain macrophage MAPKs pathway Proinflammatory mediators Anti-inflammation 

Abbreviations

BCA

Bicinchoninic acid

CNS

Central nervous system

COX-2

Cyclooxygenase-2

DAPI

4′, 6-diamidino-2-phenylindole

DMEM

Dulbecco’s modified Eagle’s medium

ERK1/2

Extracellular signal-regulated kinase1/2

FCS

Fetal calf serum

GEB

Gastrodia elata Blume

GSK-3β

Glycogen synthase kinase-3 beta

HRP

Horseradish peroxidase

IL-1β

Interleukin-1 beta

iNOS

Inducible nitric oxide synthase

JNK

c-Jun N-terminal kinase

LPS

Lipopolysaccharide

MAPKs

Mitogen-activated protein kinases

MA-5

Mitochonic acid 5

MCAO

Middle cerebral artery occlusion

NMDA

N-methyl-d-aspartate

PBS

Phosphate buffered saline

p-JNK

Phosphorylated c-Jun N-terminal kinase

p38 MAPK

p38 mitogen-activated protein kinase

p-p38

Phosphorylated p38

p-ERK1/2

Phosphorylated extracellular signal-regulated kinase1/2

PVDF

Polyvinylidene difluoride

SD rats

Sprague-Dawley rats

TNF-α

Tumor necrosis factor-alpha

AM/BM

Activated microglia/brain macrophage

Notes

Acknowledgements

This study was supported by National Natural Science Foundation of China (Project Number 31760297, Y Yuan), Applied Basic Research Projects of Yunnan Province (Project Number 2018FE001(-189)). It was also supported by Applied Basic Research Program Key Projects of Yunnan Province (Project Number 2015FA020, C-Y Wu), National Natural Science Foundation of China (Project Number 31260254, C-Y Wu).

Compliance with Ethical Standards

Conflict of interest

All authors declare that they have no conflict of interest.

Supplementary material

12017_2019_8582_MOESM1_ESM.tif (1.4 mb)
Supplementary Fig. 1 ERK2 immunofluorescence in activated microglia in MCAO rats given scutellarin treatment was not noticeably changed. Confocal images ERK2 immunofluorescence (red) was hardly detected in lectin positive AM/BM (green) in MCAO rats. Note that it is comparable to that of the same cells following scutellarin pretreatment. DAPI–blue. Scale bars = 20μm. Supplementary Material 1 (TIFF 1386 kb)
12017_2019_8582_MOESM2_ESM.tif (20.5 mb)
Supplementary Fig. 2 p38 and JNK immunofluorescence remained relatively unchanged in activated AM/BM in MCAO rats given scutellarin treatment. Confocal images showing p38 and JNK expression (red) was hardly detected in lectin positive AM/BM (green) in MCAO rat brain. Note it is comparable to that in AM/BM in MCAO rats with scutellarin treatment. DAPI–blue. Scale bars = 20μm. Supplementary Material 2 (TIFF 21040 kb)
12017_2019_8582_MOESM3_ESM.tif (1.1 mb)
Supplementary Fig. 3 Scutellarin pretreatment did not affect p38, JNK and ERK2 expression in LPS-activated BV-2 microglia. Immunofluorescence labeling and bar graphs depicting p38, JNK and ERK2 expression in LPS-activated BV-2 microglia and those with LPS + scutellarin pretreatment was comparable to that of the control BV-2 cells. DAPI – blue. Scale bars = 50μ. Supplementary Material 3 (TIFF 1126 kb)
12017_2019_8582_MOESM4_ESM.tif (13.4 mb)
Supplementary Fig. 4 Protein expression of p-p38 and p-JNK was decreased but that of p-ERK1/2 was up-regulated in MCAO 1d rat given scutellarin treatment. Western blot shows the expression level of p-p38 and p-JNK in MCAO 1d was depressed significantly at 1 day; however, the expression of p-ERK1/2 was obviously increased following treatment with scutellarin when compared with the MCAO 1d rats not treated with scutellarin. * and # represent significant differences in protein levels. P < 0.05; * when sham group is compared with MCAO 1d; # when MCAO 1d group is compared with MCAO+S 1d group. The values represent the mean ± SD in triplicate. Supplementary material 4 (TIFF 13685 kb)
12017_2019_8582_MOESM5_ESM.tif (6.7 mb)
Supplementary Fig. 5 MCAO 1d rats treated with scutellarin showed reduced p-p38 and p-JNK expression in AM/BM. Confocal images showing p-p38 and p-JNK immunofluorescence (red) in lectin positive AM/BM (green) of MCAO 1d rats and MCAO 1d rats given scutellarin treatment. A marked increase in p-p38 and p-JNK expression was evident in the AM/BM (b2-b3) in MCAO 1d rat brain; however, it was noticeably attenuated in AM/BM(c2-c3) by scutellarin treatment. Bar graph shows increased immunofluorescence in MCAO 1d rats was suppressed by scutellarin. DAPI–blue. Scale bar=75μm. * and # represent significant differences. (P < 0.05); * when sham group is compared with MCAO 1d; # when MCAO 1d group is compared with MCAO+S 1d group. The values represent the mean ± SD in triplicate. Supplementary Material 5 (TIFF 6898 kb)
12017_2019_8582_MOESM6_ESM.tif (2.3 mb)
Supplementary Fig. 6 MCAO 1d rats given scutellarin treatment showed up-regulated p-ERK1/2 expression in activated AM/BM. Confocal images showing p-ERK1/2 expression (red) in lectin positive AM/BM (green) in MCAO 1d rats (b2-b3) and following treatment with scutellarin (c2-c3). Increase in p-ERK1/2 expression was evident in the AM/BM (b3) in MCAO 1d rat. Note p-ERK1/2 expression was further augmented in AM/BM (c3) at 1 days following treatment with scutellarin. Bar graphs show expression changes of p-ERK1/2. Note its suppression in scutellarin treatment group. DAPI - blue. Scale bar = 75μm. * and # represent significant differences. (P < 0.05); * when sham group is compared with MCAO 1d; # when MCAO 1d group is compared with MCAO+S 1d group. The values represent the mean ± SD in triplicate. Supplementary Material 6 (TIFF 2392 kb)
12017_2019_8582_MOESM7_ESM.tif (13.2 mb)
Supplementary Fig. 7 Protein expression of p-p38 and p-JNK was decreased but that of p-ERK1/2 was up-regulated in MCAO 7d rat given scutellarin treatment. Western blot shows the expression level of p-p38 and p-JNK in MCAO 7d was depressed significantly at 7 day; however, the expression of p-ERK1/2 was obviously increased following treatment with scutellarin when compared with the MCAO 7d rats not treated with scutellarin. * and # represent significant differences in protein levels. P < 0.05; * when sham group is compared with MCAO 7d; # when MCAO 7d group is compared with MCAO+S 7d group. The values represent the mean ± SD in triplicate. Supplementary Material 7 (TIFF 13530 kb)
12017_2019_8582_MOESM8_ESM.tif (6.3 mb)
Supplementary Fig. 8 MCAO 7d rats treated with scutellarin showed reduced p-p38 and p-JNK expression in activated AM/BM. Confocal images showing p-p38 and p-JNK immunofluorescence (red) in lectin positive AM/BM (green) of MCAO 7d rats and MCAO 7d rats given scutellarin treatment. A marked increase in p-p38 and p-JNK expression was evident in the AM/BM (b2-b3) in MCAO 7d rat brain; however, it was noticeably attenuated in AM/BM(c2-c3) by scutellarin treatment. Bar graph shows increased immunofluorescence in MCAO 7d rats was suppressed by scutellarin. DAPI–blue. Scale bar = 75μm. * and # represent significant differences. (P < 0.05); * when sham group is compared with MCAO 7d; # when MCAO 7d group is compared with MCAO+S 7d group. The values represent the mean ± SD in triplicate. Supplementary Material 8 (TIFF 6421 kb)
12017_2019_8582_MOESM9_ESM.tif (3.6 mb)
Supplementary Fig. 9 MCAO 7d rats given scutellarin treatment showed up-regulated p-ERK1/2 expression in activated AM/BM. Confocal images showing p-ERK1/2 expression (red) in lectin positive AM/BM (green) in MCAO 7d rats (b2-b3) and following treatment with scutellarin (c2-c3). Increase in p-ERK1/2 expression was evident in the AM/BM (b3) in MCAO 7d rat. Note p-ERK1/2 expression was further augmented in AM/BM (c3) at 7 days following treatment with scutellarin. Bar graphs show expression changes of p-ERK1/2. Note its suppression in scutellarin treatment group. DAPI - blue. Scale bar = 75μm. * and # represent significant differences. (P < 0.05); * when sham group is compared with MCAO 7d; # when MCAO 7d group is compared with MCAO+S 7d group. The values represent the mean ± SD in triplicate. Supplementary Material 9 (TIFF 3657 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Hao-Lun Chen
    • 1
  • Wen-Ji Jia
    • 2
  • Hong-E Li
    • 1
  • Hong Han
    • 1
  • Fan Li
    • 3
  • Xiao-Li-Na Zhang
    • 4
  • Juan-Juan Li
    • 1
  • Yun Yuan
    • 1
    Email author
  • Chun-Yun Wu
    • 1
    Email author
  1. 1.Department of Anatomy and Histology/Embryology, School of Basic Medical SciencesKunming Medical UniversityKunmingPeople’s Republic of China
  2. 2.Department of NeurologyNo. 2 Affiliated Hospital, Kunming Medical UniversityKunmingPeople’s Republic of China
  3. 3.Department of Experiment Center for Medical Science ResearchKunming Medical UniversityKunmingPeople’s Republic of China
  4. 4.Department of Pain ManagementNo1 Affiliated Hospital, Kunming Medical UniversityKunmingPeople’s Republic of China

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