AMPK/Nrf2 signaling regulates multiple antioxidative factors and exerts neuroprotective effects. Emodin is one of the main bioactive components extracted from Polygonum multiflorum, a plant possessing important activities for human health and for treating a variety of diseases. This study examined whether emodin can activate AMPK/Nrf2 signaling and induce the expression of genes targeted by this pathway. In addition, the anti-neuroinflammatory properties of emodin in lipopolysaccharide (LPS)-stimulated microglia were examined. In microglia, the emodin treatment increased the levels of LKB1, CaMKII, and AMPK phosphorylation. Emodin increased the translocation and transactivity of Nrf2 and enhanced the levels of HO-1 and NQO1. In addition, the emodin-mediated expression of HO-1 and NQO1 was attenuated completely by an AMPK inhibitor (compound C). Moreover, emodin decreased dramatically the LPS-induced production of NO and PGE2 as well as the protein expression and promoter activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, emodin effectively inhibited the production of pro-inflammatory cytokines, TNF-α and IL-6, and reduced the level of IκBα phosphorylation, leading to the suppression of the nuclear translocation, phosphorylation, and transactivity of NF-κB. Emodin also suppressed the LPS-stimulated activation of STATs, JNK, and p38 MAPK. The anti-inflammatory effects of emodin were reversed by transfection with Nrf-2 and HO-1 siRNA and by a co-treatment with an AMPK inhibitor. These results suggest that emodin isolated from P. multiflorum can be used as a natural anti-neuroinflammatory agent that exerts its effects by inducing HO-1 and NQO1 via AMPK/Nrf2 signaling in microglia.
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Jin Q, Cheng J, Liu Y et al (2014) Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav Immun 40:131–142
Zhou X, Cao Y, Ao G et al (2014) CaMKKbeta-dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation. Antioxid Redox Signal 21:1741–1758
Chen CC, Lin JT, Cheng YF et al (2014) Amelioration of LPS-induced inflammation response in microglia by AMPK activation. Biomed Res Int 2014:692061
Lin HY, Huang BR, Yeh WL et al (2014) Antineuroinflammatory effects of lycopene via activation of adenosine monophosphate-activated protein kinase-alpha1/heme oxygenase-1 pathways. Neurobiol Aging 35:191–202
Kim SS, Lim J, Bang Y et al (2012) Licochalcone E activates Nrf2/antioxidant response element signaling pathway in both neuronal and microglial cells: therapeutic relevance to neurodegenerative disease. J Nutr Biochem 23:1314–1323
Lee IS, Lim J, Gal J et al (2011) Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells. Neurochem Int 58:153–160
Parada E, Buendia I, Navarro E et al (2015) Microglial HO-1 induction by curcumin provides antioxidant, antineuroinflammatory, and glioprotective effects. Mol Nutr Food Res 59:1690–1700
Mo C, Wang L, Zhang J et al (2014) The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid Redox Signal 20:574–588
Lee J, Kim S (2014) Upregulation of heme oxygenase-1 expression by dehydrodiconiferyl alcohol (DHCA) through the AMPK-Nrf2 dependent pathway. Toxicol Appl Pharmacol 281:87–100
Liu JT, Chen BY, Zhang JQ et al (2015) Lead exposure induced microgliosis and astrogliosis in hippocampus of young mice potentially by triggering TLR4-MyD88-NFkappaB signaling cascades. Toxicol Lett 239:97–107
ElAli A, Rivest S (2015) Microglia in alzheimer’s disease: a multifaceted relationship. Brain Behav Immun 55:138–150
Masson GS, Nair AR, Dange RB et al (2015) Toll-like receptor 4 promotes autonomic dysfunction, inflammation and microglia activation in the hypothalamic paraventricular nucleus: role of endoplasmic reticulum stress. PLoS One 10:e0122850
Velagapudi R, Aderogba M, Olajide OA (2014) Tiliroside, a dietary glycosidic flavonoid, inhibits TRAF-6/NF-kappaB/p38-mediated neuroinflammation in activated BV2 microglia. Biochim Biophys Acta 1840:3311–3319
Zeng KW, Yu Q, Song FJ et al (2015) Deoxysappanone B, a homoisoflavone from the chinese medicinal plant caesalpinia sappan L., protects neurons from microglia-mediated inflammatory injuries via inhibition of IkappaB kinase (IKK)-NF-kappaB and p38/ERK MAPK pathways. Eur J Pharmacol 748:18–29
Huang BP, Lin CH, Chen HM et al (2015) AMPK activation inhibits expression of proinflammatory mediators through downregulation of PI3K/p38 MAPK and NF-kappaB signaling in murine macrophages. DNA Cell Biol 34:133–141
Kacimi R, Giffard RG, Yenari MA (2011) Endotoxin-activated microglia injure brain derived endothelial cells via NF-kappaB, JAK-STAT and JNK stress kinase pathways. J Inflamm (Lond) 8:7-9255-8-7
Park J, Min JS, Kim B et al (2015) Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways. Neurosci Lett 584:191–196
Ahn SM, Kim YR, Kim HN et al (2015) Beneficial effects of polygonum multiflorum on hippocampal neuronal cells and mouse focal cerebral ischemia. Am J Chin Med 43:637–651
Chen G, Zhang J, Zhang H et al (2015) Anti-inflammatory effect of emodin on lipopolysaccharide-induced keratitis in wistar rats. Int J Clin Exp Med 8:12382–12389
Wang Y, Yu H, Zhang J et al (2015) Anti-tumor effect of emodin on gynecological cancer cells. Cell Oncol (Dordr) 38:353–363
Liu R, Li A, Sun A (2004) Preparative isolation and purification of hydroxyanthraquinones and cinnamic acid from the chinese medicinal herb rheum officinale baill. By high-speed counter-current chromatography. J Chromatogr A 1052:217–221
Yang Z, Zhou E, Wei D et al (2014) Emodin inhibits LPS-induced inflammatory response by activating PPAR-gamma in mouse mammary epithelial cells. Int Immunopharmacol 21:354–360
Tang T, Yin L, Yang J et al (2007) Emodin, an anthraquinone derivative from rheum officinale baill, enhances cutaneous wound healing in rats. Eur J Pharmacol 567:177–185
Giulian D, Baker TJ (1986) Characterization of ameboid microglia isolated from developing mammalian brain. J Neurosci 6:2163–2178
Min KJ, Jang JH, Kwon TK (2012) Inhibitory effects of melatonin on the lipopolysaccharide-induced CC chemokine expression in BV2 murine microglial cells are mediated by suppression of akt-induced NF-kappaB and STAT/GAS activity. J Pineal Res 52:296–304
Przanowski P, Dabrowski M, Ellert-Miklaszewska A et al (2014) The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia. J Mol Med (Berl) 92:239–254
Song P, Kim JH, Ghim J et al (2013) Emodin regulates glucose utilization by activating AMP-activated protein kinase. J Biol Chem 288:5732–5742
Guo H, Shen X, Xu Y et al (2013) Emodin prevents hypoxic-ischemic neuronal injury: involvement of the activin A pathway. Neural Regen Res 8:1360–1367
Wu Y, Tu X, Lin G et al (2007) Emodin-mediated protection from acute myocardial infarction via inhibition of inflammation and apoptosis in local ischemic myocardium. Life Sci 81:1332–1338
Jayasooriya RG, Lee KT, Lee HJ et al (2014) Anti-inflammatory effects of beta-hydroxyisovalerylshikonin in BV2 microglia are mediated through suppression of the PI3K/akt/NF-kB pathway and activation of the Nrf2/HO-1 pathway. Food Chem Toxicol 65:82–89
Kang CH, Choi YH, Moon SK et al (2013) Quercetin inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-kappaB pathway and activating the Nrf2-dependent HO-1 pathway. Int Immunopharmacol 17:808–813
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2015R1D1A1A01059450). This research was supported by the High Value-added Food Technology Development Program (314043-03-1-HD020), Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea.
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Park, S.Y., Jin, M.L., Ko, M.J. et al. Anti-neuroinflammatory Effect of Emodin in LPS-Stimulated Microglia: Involvement of AMPK/Nrf2 Activation. Neurochem Res 41, 2981–2992 (2016). https://doi.org/10.1007/s11064-016-2018-6