Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

β-Lapachone suppresses neuroinflammation by modulating the expression of cytokines and matrix metalloproteinases in activated microglia

Authors: Eun-Jung Lee, Hyun-Myung Ko, Yeon-Hui Jeong, Eun-Mi Park, Hee-Sun Kim

Published in: Journal of Neuroinflammation | Issue 1/2015

Login to get access

Abstract

Background

β-Lapachone (β-LAP) is a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia sp.), and it has been used for treatment of rheumatoid arthritis, infection, and cancer. In the present study, we investigated whether β-LAP has anti-inflammatory effects under in vitro and in vivo neuroinflammatory conditions.

Methods

The effects of β-LAP on the expression of inducible nitric oxide synthase (iNOS), cytokines, and matrix metalloproteinases (MMPs) were examined in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and rat primary microglia by ELISA, reverse transcription polymerase chain reaction (RT-PCR), and Western blot analysis. Microglial activation and the expression levels of proinflammatory molecules were measured in the LPS-injected mouse brain by immunohistochemistry and RT-PCR analysis. The detailed molecular mechanism underlying the anti-inflammatory effects of β-LAP was analyzed by electrophoretic mobility shift assay, reporter gene assay, Western blot, and RT-PCR analysis.

Results

β-LAP inhibited the expression of iNOS, proinflammatory cytokines, and MMPs (MMP-3, MMP-8, MMP-9) at mRNA and protein levels in LPS-stimulated microglia. On the other hand, β-LAP upregulated the expressions of anti-inflammatory molecules such as IL-10, heme oxygenase-1 (HO-1), and the tissue inhibitor of metalloproteinase-2 (TIMP-2). The anti-inflammatory effect of β-LAP was confirmed in an LPS-induced systemic inflammation mouse model. Thus, β-LAP inhibited microglial activation and the expressions of iNOS, proinflammatory cytokines, and MMPs in the LPS-injected mouse brain. Further mechanistic studies revealed that β-LAP exerts anti-inflammatory effects by inhibiting MAPKs, PI3K/AKT, and NF-κB/AP-1 signaling pathways in LPS-stimulated microglia. β-LAP also inhibited reactive oxygen species (ROS) production by suppressing the expression and/or phosphorylation of NADPH oxidase subunit proteins, such as p47phox and gp91phox. The anti-oxidant effects of β-LAP appeared to be related with the increase of HO-1 and NQO1 via the Nrf2/anti-oxidant response element (ARE) pathway and/or the PKA pathway.

Conclusions

The strong anti-inflammatory/anti-oxidant effects of β-LAP may provide preventive therapeutic potential for various neuroinflammatory disorders.
Appendix
Available only for authorised users
Literature
1.
Gomez-Nicola D, Perry VH. Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neuroscientist. 2015;21:169–84.PubMedCentralPubMedCrossRef
2.
Tremblay MÈ, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A. The role of microglia in the healthy brain. J Neurosci. 2011;31:16064–9.PubMedCrossRef
3.
4.
Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:1387–94.PubMedCrossRef
5.
6.
Norden DM, Muccigrosso MM, Godbout JP. Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology. 2014;96:29–41.PubMedCrossRef
7.
Schaffner-Sabba K, Schmidt-Ruppin KH, Wehrli W, Schuerch AR, Wasley JW. beta-Lapachone: synthesis of derivatives and activities in tumor models. J Med Chem. 1984;27:990–4.PubMedCrossRef
8.
de Castro SL, Emery FS, da Silva Junior EN. Synthesis of quinoidal molecules: strategies towards bioactive compounds with an emphasis of lapachones. Eur J Med Chem. 2013;69:678–700.PubMedCrossRef
9.
Gomez Castellanos JR, Prieto JM, Heinrich M. Red lapacho (Tabebuia impetiginosa)—a global ethnopharmacological commodity? J Ethnopharmacol. 2009;121:1–13.PubMedCrossRef
10.
Pardee AB, Li YZ, Li CJ. Cancer therapy with β-lapachone. Curr Cancer Drug Targets. 2002;2:227–42.PubMedCrossRef
11.
Kung HN, Lu KS, Chau YP. The chemotherapeutic effects of lapacho tree extract: β-lapachone. Chemotherapy. 2014;3:2.
12.
Reinicke KE, Bey EA, Bentle MS, Pink JJ, Ingalls ST, Hoppel CL, et al. Development of beta-lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels. Clin Cancer Res. 2005;11:3055–64.PubMedCrossRef
13.
Yu HY, Kim SO, Jin GY, Kim GY, Kim WJ, Yoo YH, et al. β-Lapachone-induced apoptosis of human gastric carcinoma AGS cells is caspase-dependent and regulated by the PI3K/Akt pathway. Biomol Ther (Seoul). 2014;22:184–92.CrossRef
14.
Hueber A, Esser P, Heimann K, Kociok N, Wineter S, Weller M. The topoisomerase I inhibitors, camptothecin and β-lapachone, induce apoptosis of human retinal pigment epithelial cells. Exp Eye Res. 1998;67:525–30.PubMedCrossRef
15.
Oh GS, Kim HJ, Choi JH, Shen A, Choe SK, Karna A, et al. Pharmacological activation of NQO1 increases NAD+ levels and attenuates cisplatin-mediated acute kidney injury in mice. Kidney Int. 2014;85:547–60.PubMedCentralPubMedCrossRef
16.
Tzeng HP, Ho FM, Chao KF, Kuo ML, Lin-Shiau SY, Liu SH. beta-Lapachone reduces endotoxin-induced macrophage activation and lung edema and mortality. Am J Respir Crit Care Med. 2003;168:85–91.PubMedCrossRef
17.
Sitônio MM, Carvalho Júnior CH, Campos Ide A, Silva JB, Lima Mdo C, Góes AJ, et al. Anti-inflammatory and anti-arthritic activities of 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione(β-lapachone). Inflamm Res. 2013;62:107–13.PubMedCrossRef
18.
Byun SJ, Son Y, Hwan Cho B, Chung HT, Pae HO. β-Lapachone, a substrate of NAD(P)H:quinone oxidoreductase, induces anti-inflammatory heme oxygenase-1 via AMP-activated protein kinase activation in RAW264.7 macrophages. J Clin Biochem Nutr. 2013;52:106–11.PubMedCentralPubMedCrossRef
19.
Byun SJ, Son Y, Pae HO. Cytoprotective effect of β-lapachone by inducing heme oxygenase-1 expression and AMP-activated protein kinase activation in human endothelial cells. Eur Rev Med Pharmacol Sci. 2014;18:949–58.PubMed
20.
Moon DO, Choi YH, Kim ND, Park YM, Kim GY. Anti-inflammatory effects of beta-lapachone in lipopolysaccharide-stimulated BV2 microglia. Int Immunopharmacol. 2007;7:506–14.PubMedCrossRef
21.
Lee EJ, Woo MS, Moon PG, Baek MC, Choi IY, Kim WK, et al. α-Synuclein activates microglia by inducing the expressions of matrix metalloproteases and the subsequent activation of protease-activated receptor-1. J Immunol. 2010;185:615–23.PubMedCrossRef
22.
Lee EJ, Han JE, Woo MS, Shin JA, Park EM, Kang JL, et al. Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-α activation. J Immunol. 2014;193:2384–93.PubMedCrossRef
23.
Woo MS, Park JS, Choi IY, Kim WK, Kim HS. Inhibition of MMP-3 or -9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and iNOS in microglia. J Neurochem. 2008;106:770–80.PubMedCrossRef
24.
Bocchini V, Mazzolla R, Barluzzi R, Blasi E, Sick P, Kettenmann H. An immortalized cell line expresses properties of activated microglial cells. J Neurosci Res. 1992;31:616–21.PubMedCrossRef
25.
Lee KM, Kang HS, Yun CH, Kwak HS. Potential in vitro protective effect of quercetin, catechin, caffeic acid and phytic acid against ethanol-induced oxidative stress in SK-Hep-1 cells. Biomol Ther (Seoul). 2012;20:492–8.CrossRef
26.
Jung JS, Shin KO, Lee YM, Shin JA, Park EM, Jeong J, et al. Anti-inflammatory mechanism of exogenous C2 ceramide in lipopolysaccharide-stimulated microglia. Biochim Biophys Acta. 2013;1831:1016–26.PubMedCrossRef
27.
Li MH, Cha YN, Surh YJ. Peroxynitrite induces HO-1 expression via PI3K/Akt-dependent activation of NF-E2-related factor 2 in PC12 cells. Free Rad Biol Med. 2006;41:1079–91.PubMedCrossRef
28.
Lee JM, Moehlenkamp JD, Hanson JM, Johnson JA. Nrf2-dependent activation of the antioxidant response elements by tert-butylhydroquinone is independent of oxidative stress in IMR-32 human neuroblastoma cells. Biochem Biophys Res Commun. 2001;280:286–92.PubMedCrossRef
29.
Lee EJ, Kim HS. The anti-inflammatory role of tissue inhibitor of metalloproteinase-2 in lipopolysaccharide-stimulated microglia. J Neuroinflammation. 2014;11:116.PubMedCentralPubMedCrossRef
30.
Kim WK, Hwang SY, Oh ES, Piao HZ, Kim KW, Han IO. TGF-beta1 represses activation and resultant death of microglia via inhibition of phosphatidylinositol 3-kinase activity. J Immunol. 2004;172:7015–23.PubMedCrossRef
31.
Van Eldik LJ, Thompson WL, Ralay Ranaivo H, Behanna HA, Martin Watterson D. Glia proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative diseases: function-based and target-based discovery approaches. Int Rev Neurobiol. 2007;82:277–96.PubMedCrossRef
32.
Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87:245–313.PubMedCrossRef
33.
34.
35.
Jung JS, Shin JA, Park EM, Lee JE, Kang YS, Min SW, et al. Anti-inflammatory mechanism of ginsenoside Rh1 in lipopolysaccharide-stimulated microglia: critical role of the protein kinase A pathway and hemeoxygenase-1 expression. J Neurochem. 2010;115:1668–80.PubMedCrossRef
36.
Lee B, Cao R, Choi YS, Cho HY, Rhee AD, Hah CK, et al. The CREB/CRE transcriptional pathway: protection against oxidative stress-mediated neuronal cell death. J Neurochem. 2009;108:1251–65.PubMedCentralPubMedCrossRef
37.
38.
Agrawal SM, Lau L, Yong VW. MMPs in the central nervous system: where the good guys go bad. Semin Cell Dev Biol. 2008;19:42–51.PubMedCrossRef
39.
Morancho A, Rosell A, García-Bonilla L, Montaner J. Matrix metalloproteinase and stroke infarct size: role for anti-inflammatory treatment. Ann N Y Acad Sci. 2010;1207:123–33.PubMedCrossRef
40.
Rosenberg GA. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 2009;8:205–16.PubMedCrossRef
41.
Kansanen E, Jykkanen HK, Levonen AL. Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids. Free Rad Biol Med. 2012;52:973–82.PubMedCrossRef
42.
Yang MS, Min KJ, Joe E. Multiple mechanisms that prevent excessive brain inflammation. J Neurosci Res. 2007;85:2298–305.PubMedCrossRef
43.
Syapin PJ. Regulation of heme oxygenase-1 for treatment of neuroinflammation and brain disorders. Brit J Pharmacol. 2008;155:623–40.CrossRef
44.
Juncos JP, Tracz MJ, Croatt AJ, Grande JP, Ackerman AW, Katusic ZS, et al. Genetic deficiency of heme oxygenase-1 impairs functionality and form of an arteriovenous fistula in the mouse. Kidney Int. 2008;74:47–51.PubMedCentralPubMedCrossRef
45.
Hwang JH, Kim DW, Jo EJ, Kim YK, Jo YS, Park JH, et al. Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice. Diabetes. 2009;58:965–74.PubMedCentralPubMedCrossRef
46.
Kim SY, Jeoung NH, Oh CJ, Choi YK, Lee HJ, Kim HJ, et al. Activation of NAD(P)H:quinone oxidoreductase 1 prevents arterial restenosis by suppressing vascular smooth muscle cell proliferation. Circ Res. 2009;104:842–50.PubMedCrossRef
47.
Kim YH, Hwang JH, Noh JR, Gang GT, Tadi S, Yim YH, et al. Prevention of salt-induced renal injury by activation of NAD(P)H:quinone oxidoreductase 1, associated with NADPH oxidase. Free Radic Biol Med. 2012;52:880–8.PubMedCrossRef
48.
Kim YH, Hwang JH, Kim KS, Noh JR, Gang GT, Seo Y, et al. NAD(P)H:quinone oxidoreductase 1 activation reduces blood pressure through regulation of endothelial nitric oxide synthase acetylation in spontaneously hypertensive rats. Am J Hypertens. 2015;28:50–7.PubMedCrossRef
49.
Jackson JK, Higo T, Hunter WL, Burt HM. Topoisomerase inhibitors as anti-arthritic agents. Inflamm Res. 2008;57:126–34.PubMedCrossRef
50.
Gang GT, Hwang JH, Kim YH, Noh JR, Kim KS, Jeong JY, et al. Protection of NAD(P)H:quinone oxidoreductase 1 against renal ischemia/reperfusion injury in mice. Free Radic Biol Med. 2014;67:139–49.PubMedCrossRef
51.
Lee JS, Park AH, Lee SH, Lee SH, Kim JH, Yang SJ, et al. beta-Lapachone, a modulator of NAD metabolism, prevents health declines in aged mice. PLoS ONE. 2012;7:e47122.PubMedCentralPubMedCrossRef
Metadata
Title
β-Lapachone suppresses neuroinflammation by modulating the expression of cytokines and matrix metalloproteinases in activated microglia
Authors
Eun-Jung Lee
Hyun-Myung Ko
Yeon-Hui Jeong
Eun-Mi Park
Hee-Sun Kim
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0355-z

Other articles of this Issue 1/2015

Journal of Neuroinflammation 1/2015 Go to the issue

Research

Self-reactive CD4+ T cells activated during viral-induced demyelination do not prevent clinical recovery

Research

Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide (PACAP)

Research

Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans

Research

Crosstalk between macrophages and astrocytes affects proliferation, reactive phenotype and inflammatory response, suggesting a role during reactive gliosis following spinal cord injury

Review

Mapping neuroinflammation in frontotemporal dementia with molecular PET imaging

Research

NT-020 treatment reduces inflammation and augments Nrf-2 and Wnt signaling in aged rats