Evodiamine Inhibits Lipopolysaccharide (LPS)-Induced Inflammation in BV-2 Cells via Regulating AKT/Nrf2-HO-1/NF-κB Signaling Axis

Abstract

Neuroinflammation is caused by excessive activation of microglia and plays an essential role in neurodegenerative diseases. After activation, microglia produce several kinds of inflammatory mediators, trigger an excessive inflammatory response, and ultimately destroy the surrounding neurons. Therefore, agents that inhibit neuroinflammation may be potential drug candidates for neurodegenerative diseases. Evodiamine (EV) has anti-inflammatory functions in peripheral tissues. However, whether EV exerts the same function in neuroinflammation is not known. In the present study, the aim was to explore whether EV attenuates microglial overactivation and therefore suppresses the development of neuroinflammation in lipopolysaccharide (LPS)-stimulated BV-2 cells. It was found that EV effectively inhibited expression of proinflammatory mediators (cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)) via AKT/Nrf2/HO-1 activation and suppressed NF-κB p65 phosphorylation. In addition, EV could suppress LPS-induced inflammatory response and loss of dopaminergic neuron in mouse mesencephalic neuron--glia cells. Hence, these findings demonstrate that EV suppresses neuroinflammation caused by overactivated microglia via regulating the AKT/Nrf2/HO-1/NF-κB signaling axis.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Abbreviations

EV:

Evodiamine

LPS:

Lipopolysaccharide

AKT:

Protein kinase B

Nrf2:

Nuclear factor erythroid 2-related factor 2

HO-1:

Heme oxygenase-1

NF-κB:

Nuclear transcription factor-κB

References

  1. Amor S, Puentes F, Baker D, van der Valk P (2010) Inflammation in neurodegenerative diseases. Immunology 129:154–169. https://doi.org/10.1111/j.1365-2567.2009.03225.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Bedi SS, Smith P, Hetz RA, Xue H, Cox CS (2013) Immunomagnetic enrichment and flow cytometric characterization of mouse microglia. J Neurosci Methods 219:176–182. https://doi.org/10.1016/j.jneumeth.2013.07.017

    CAS  Article  PubMed  Google Scholar 

  3. Bilbo SD (2010) Early-life infection is a vulnerability factor for aging-related glial alterations and cognitive decline. Neurobiol Learn Mem 94:57–64. https://doi.org/10.1016/j.nlm.2010.04.001

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cai QY, Li WR, Wei JJ, Mi SQ, Wang NS (2014) Antinociceptive activity of aqueous and alcohol extract of evodia rutaecarpa. Indian J Pharm Sci 76:235–239

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Cannon JR, Greenamyre JT (2011) The role of environmental exposures in neurodegeneration and neurodegenerative diseases. Toxicol Sci 124:225–250. https://doi.org/10.1093/toxsci/kfr239

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Chang Y, Kong R (2019) Ganoderic acid A alleviates hypoxia-induced apoptosis, autophagy, and inflammation in rat neural stem cells through the PI3K/AKT/mTOR pathways. Phytother Res 33:1448–1456. https://doi.org/10.1002/ptr.6336

    CAS  Article  PubMed  Google Scholar 

  7. Chen G et al. (2017) Galangin reduces the loss of dopaminergic neurons in an LPS-evoked model of Parkinson’s disease in rats. Int J Mol Sci 19 doi:10.3390/ijms19010012

  8. Chen YH, Yet SF, Perrella MA (2003) Role of heme oxygenase-1 in the regulation of blood pressure and cardiac function. Exp Biol Med (Maywood) 228:447–453. https://doi.org/10.1177/15353702-0322805-03

    CAS  Article  Google Scholar 

  9. Chun JM, Nho KJ, Kim HS, Lee AY, Moon BC, Kim HK (2014) An ethyl acetate fraction derived from Houttuynia cordata extract inhibits the production of inflammatory markers by suppressing NF-small ka, CyrillicB and MAPK activation in lipopolysaccharide-stimulated RAW 264.7 macrophages BMC complement. Altern Med 14:234. https://doi.org/10.1186/1472-6882-14-234

    Article  Google Scholar 

  10. Fletcher EV et al (2017) Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy. Nat Neurosci 20:905–916. https://doi.org/10.1038/nn.4561

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Fu SP et al (2015) Anti-inflammatory effects of BHBA in both in vivo and in vitro Parkinson’s disease models are mediated by GPR109A-dependent mechanisms. J Neuroinflamm 12:9. https://doi.org/10.1186/s12974-014-0230-3

    CAS  Article  Google Scholar 

  12. He D et al. (2018) Tubeimoside I protects dopaminergic neurons against inflammation-mediated damage in lipopolysaccharide (LPS)-evoked model of Parkinson’s disease in rats. Int J Mol Sci 19. doi:10.3390/ijms19082242

  13. Herrera AJ, Castano A, Venero JL, Cano J, Machado A (2000) The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system. Neurobiol Dis 7:429–447. https://doi.org/10.1006/nbdi.2000.0289

    CAS  Article  PubMed  Google Scholar 

  14. Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8:382–397. https://doi.org/10.1016/S1474-4422(09)70062-6

    CAS  Article  PubMed  Google Scholar 

  15. Hu CY, Wu HT, Su YC, Lin CH, Chang CJ, Wu CL (2017) Evodiamine exerts an anti-hepatocellular carcinoma activity through a WWOX-dependent pathway molecules 22. doi:10.3390/molecules22071175

  16. Huang B et al (2018) Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson’s Disease via Regulation of the AKT/GSK3beta-Nrf2/NF-kappaB Signaling. Axis Front Immunol 9:2527. https://doi.org/10.3389/fimmu.2018.02527

    CAS  Article  PubMed  Google Scholar 

  17. Huang J et al (2015) Antiproliferation effect of evodiamine in human colon cancer cells is associated with IGF-1/HIF-1alpha downregulation. Oncol Rep 34:3203–3211. https://doi.org/10.3892/or.2015.4309

    CAS  Article  PubMed  Google Scholar 

  18. Hurley SD, O’Banion MK, Song DD, Arana FS, Olschowka JA, Haber SN (2003) Microglial response is poorly correlated with neurodegeneration following chronic, low-dose MPTP administration in monkeys. Exp Neurol 184:659–668. https://doi.org/10.1016/S0014-4886(03)00273-5

    CAS  Article  PubMed  Google Scholar 

  19. Iranzo A (2016) Sleep in Neurodegenerative Diseases. Sleep Med Clin 11:1–18. https://doi.org/10.1016/j.jsmc.2015.10.011

    Article  PubMed  Google Scholar 

  20. Jeohn GH et al (2002) p38 MAP kinase is involved in lipopolysaccharide-induced dopaminergic neuronal cell death in rat mesencephalic neuron-glia cultures. Ann N Y Acad Sci 962:332–346. https://doi.org/10.1111/j.1749-6632.2002.tb04078.x

    CAS  Article  PubMed  Google Scholar 

  21. Jewett M, Jimenez-Ferrer I, Swanberg M (2017) Astrocytic expression of GSTA4 is associated to dopaminergic neuroprotection in a Rat 6-OHDA model of Parkinson’s disease Brain Sci 7. doi:10.3390/brainsci7070073

  22. Khanam H, Ali A, Asif M, Shamsuzzaman (2016) Neurodegenerative diseases linked to misfolded proteins and their therapeutic approaches: a review. Eur J Med Chem 124:1121–1141. https://doi.org/10.1016/j.ejmech.2016.08.006

    CAS  Article  PubMed  Google Scholar 

  23. Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. https://doi.org/10.1038/nature21029

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795. https://doi.org/10.1038/nature05292

    CAS  Article  PubMed  Google Scholar 

  25. Martins IJ (2015) Overnutrition determines LPS regulation of mycotoxin induced neurotoxicity in neurodegenerative diseases. Int J Mol Sci 16:29554–29573. https://doi.org/10.3390/ijms161226190

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Mazon JN, de Mello AH, Ferreira GK, Rezin GT (2017) The impact of obesity on neurodegenerative diseases. Life Sci 182:22–28. https://doi.org/10.1016/j.lfs.2017.06.002

    CAS  Article  PubMed  Google Scholar 

  27. Miklossy J, Doudet DD, Schwab C, Yu S, McGeer EG, McGeer PL (2006) Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp Neurol 197:275–283. https://doi.org/10.1016/j.expneurol.2005.10.034

    CAS  Article  PubMed  Google Scholar 

  28. Mohan V, Agarwal R, Singh RP (2016) A novel alkaloid, evodiamine causes nuclear localization of cytochrome-c and induces apoptosis independent of p53 in human lung cancer cells. Biochem Biophys Res Commun 477:1065–1071. https://doi.org/10.1016/j.bbrc.2016.07.037

    CAS  Article  PubMed  Google Scholar 

  29. Mrvova N, Skandik M, Kuniakova M, Rackova L (2015) Modulation of BV-2 microglia functions by novel quercetin pivaloyl ester. Neurochem Int 90:246–254. https://doi.org/10.1016/j.neuint.2015.09.005

    CAS  Article  PubMed  Google Scholar 

  30. Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291–13295. https://doi.org/10.1074/jbc.R900010200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Norden DM, Muccigrosso MM, Godbout JP (2015) Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology 96:29–41. https://doi.org/10.1016/j.neuropharm.2014.10.028

    CAS  Article  PubMed  Google Scholar 

  32. Pittala V, Salerno L, Romeo G, Modica MN, Siracusa MA (2013) A focus on heme oxygenase-1 (HO-1) inhibitors. Curr Med Chem 20:3711–3732. https://doi.org/10.2174/0929867311320300003

    CAS  Article  PubMed  Google Scholar 

  33. Qin L et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462. https://doi.org/10.1002/glia.20467

    Article  PubMed  PubMed Central  Google Scholar 

  34. Rosa AI et al (2018) Tauroursodeoxycholic acid improves motor symptoms in a mouse model of Parkinson’s disease. Mol Neurobiol 55:9139–9155. https://doi.org/10.1007/s12035-018-1062-4

    CAS  Article  PubMed  Google Scholar 

  35. Spires-Jones TL, Attems J, Thal DR (2017) Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol 134:187–205. https://doi.org/10.1007/s00401-017-1709-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Tran C et al. (2019) Sphingosine 1-phosphate but not Fingolimod protects neurons against excitotoxic cell death by inducing neurotrophic gene expression in astrocytes. J Neurochem e14917. doi:10.1111/jnc.14917

  37. Wang XX et al (2013) Quinolone alkaloids with antibacterial and cytotoxic activities from the fruits of Evodia rutaecarpa. Fitoterapia 89:1–7. https://doi.org/10.1016/j.fitote.2013.04.007

    CAS  Article  PubMed  Google Scholar 

  38. Wei J, Ching LC, Zhao JF, Shyue SK, Lee HF, Kou YR, Lee TS (2013) Essential role of transient receptor potential vanilloid type 1 in evodiamine-mediated protection against atherosclerosis. Acta Physiol (Oxf) 207:299–307. https://doi.org/10.1111/apha.12005

    CAS  Article  Google Scholar 

  39. Wei L, Jin X, Cao Z, Li W (2016) Evodiamine induces extrinsic and intrinsic apoptosis of ovarian cancer cells via the mitogen-activated protein kinase/phosphatidylinositol-3-kinase/protein kinase B signaling pathways. J Tradit Chin Med 36:353–359. https://doi.org/10.1016/s0254-6272(16)30049-8

    Article  PubMed  Google Scholar 

  40. Wu JY et al (2013) Topoisomerase I inhibitor evodiamine acts as an antibacterial agent against drug-resistant Klebsiella pneumoniae. Planta Med 79:27–29. https://doi.org/10.1055/s-0032-1327925

    CAS  Article  PubMed  Google Scholar 

  41. Yan J et al (2018) Nrf2 protects against acute lung injury and inflammation by modulating TLR4 and Akt signaling. Free Radic Biol Med 121:78–85. https://doi.org/10.1016/j.freeradbiomed.2018.04.557

    CAS  Article  PubMed  Google Scholar 

  42. Yu H, Jin H, Gong W, Wang Z, Liang H (2013) Pharmacological actions of multi-target-directed evodiamine. Molecules 18:1826–1843. https://doi.org/10.3390/molecules18021826

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Zhang YN, Yang YF, Yang XW (2018) Blood-brain barrier permeability and neuroprotective effects of three main alkaloids from the fruits of Euodia rutaecarpa with MDCK-pHaMDR cell monolayer and PC12 cell line. Biomed Pharmacother 98:82–87. https://doi.org/10.1016/j.biopha.2017.12.017

    CAS  Article  PubMed  Google Scholar 

  44. Zhao Z, Gong S, Wang S, Ma C (2015) Effect and mechanism of evodiamine against ethanol-induced gastric ulcer in mice by suppressing Rho/NF-small ka CyrillicB pathway. Int Immunopharmacol 28:588–595. https://doi.org/10.1016/j.intimp.2015.07.030

    CAS  Article  PubMed  Google Scholar 

  45. Zhou P et al (2019) Evodiamine inhibits migration and invasion by Sirt1-mediated post-translational modulations in colorectal cancer. Anticancer Drugs 30:611–617. https://doi.org/10.1097/CAD.0000000000000760

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was funded by National Natural Science Foundation of China (project No. 31772547, 31702211), Jilin Scientific and Technological Development Program (project No. 20170623083-04TC), and JLU Science and Technology Innovative Research Team (project No. 201910183X588, 201910183811).

Author information

Affiliations

Authors

Contributions

TM, SF, DH, and GH performed most of the experiments, analyzed the results, and wrote the manuscript. DL conceived and designed this study and analyzed the data. They were involved in all aspects of the study read and modified the manuscript. XG, YZ, BH, JD, AZ, and YS also participated in the research. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Dianfeng Liu.

Ethics declarations

Conflicts of interest

The authors declare no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors. The study complies with current ethical consideration.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Meng, T., Fu, S., He, D. et al. Evodiamine Inhibits Lipopolysaccharide (LPS)-Induced Inflammation in BV-2 Cells via Regulating AKT/Nrf2-HO-1/NF-κB Signaling Axis. Cell Mol Neurobiol 41, 115–127 (2021). https://doi.org/10.1007/s10571-020-00839-w

Download citation

Keywords

  • Evodiamine
  • Microglia
  • Neuroinflammation
  • Neurodegenerative disease