Abstract
Recent studies showed that the activation of toll-like receptor 4 (TLR4) on dorsal root ganglion (DRG) neurons might underlie neuropathic and inflammatory pain states. This study was undertaken to investigate the effects of wogonin, a flavonoid with potent anti-inflammatory properties on the inflammatory reaction and TLR4 dependent pathways in lipopolysaccharide (LPS)-treated DRG neurons. Our results showed that wogonin not only inhibited the expression and interaction of TLR4, MyD88, and TAK1, but also reduced the activation of nuclear factor kappa B and mitogen-activated protein kinases pathway in LPS-treated DRG neurons. Moreover, wogonin significantly suppressed the release of pro-inflammatory mediators in LPS-induced DRG neurons, including cyclooxygenase-2, inducible nitric oxide synthases, interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha. Our results suggested that pre-treatment with wogonin could attenuate the TLR4-mediated inflammatory response in LPS-induced DRG neurons, thus might be beneficial for the treatment of neuropathic and inflammatory pain.
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References
Cao L, Tanga FY, Deleo JA (2009) The contributing role of CD14 in toll-like receptor 4 dependent neuropathic pain. Neuroscience 158:896–903
Chen CC, Hung TH, Wang YH, Lin CW, Wang PY, Lee CY, Chen SF (2012) Wogonin improves histological and functional outcomes, and reduces activation of TLR4/NF-kappaB signaling after experimental traumatic brain injury. PLoS ONE 7:e30294
Chi YS, Lim H, Park H, Kim HP (2003) Effects of wogonin, a plant flavone from Scutellaria radix, on skin inflammation: in vivo regulation of inflammation-associated gene expression. Biochem Pharmacol 66:1271–1278
De Leo JA, Tawfik VL, LaCroix-Fralish ML (2006) The tetrapartite synapse: path to CNS sensitization and chronic pain. Pain 122:17–21
Deng W, Jiang D, Fang Y, Zhou H, Cheng Z, Lin Y, Zhang R, Zhang J, Pu P, Liu Y, Bian Z, Tang Q (2013) Hesperetin protects against cardiac remodelling induced by pressure overload in mice. J Mol Histol 44:575–585
Fenzi F, Benedetti MD, Moretto G, Rizzuto N (2001) Glial cell and macrophage reactions in rat spinal ganglion after peripheral nerve lesions: an immunocytochemical and morphometric study. Arch Ital Biol 139:357–365
Huang WH, Lee AR, Yang CH (2006) Antioxidative and anti-inflammatory activities of polyhydroxyflavonoids of Scutellaria baicalensis GEORGI. Biosci Biotechnol Biochem 70:2371–2380
Huang GC, Chow JM, Shen SC, Yang LY, Lin CW, Chen YC (2007) Wogonin but not Nor-wogonin inhibits lipopolysaccharide and lipoteichoic acid-induced iNOS gene expression and NO production in macrophages. Int Immunopharmacol 7:1054–1063
Hutchinson MR, Ramos KM, Loram LC, Wieseler J, Sholar PW, Kearney JJ, Lewis MT, Crysdale NY, Zhang Y, Harrison JA, Maier SF, Rice KC, Watkins LR (2009) Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats. Neuroscience 164:1821–1832
Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Zhang YQ (2007) Protein kinases as potential targets for the treatment of pathological pain. Handb Exp Pharmacol 177:359–389
Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:24–32
Kuang X, Huang Y, Gu HF, Zu XY, Zou WY, Song ZB, Guo QL (2012) Effects of intrathecal epigallocatechin gallate, an inhibitor of toll-like receptor 4, on chronic neuropathic pain in rats. Eur J Pharmacol 676:51–56
Laedermann CJ, Cachemaille M, Kirschmann G, Pertin M, Gosselin RD, Chang I, Albesa M, Towne C, Schneider BL, Kellenberger S, Abriel H, Decosterd I (2013) Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain. J Clin Invest 123:3002–3013
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA 100:8514–8519
Leow-Dyke S, Allen C, Denes A, Nilsson O, Maysami S, Bowie AG, Rothwell NJ, Pinteaux E (2012) Neuronal toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro. J Neuroinflammation 9:230
Lin YC, Huang DY, Chu CL, Lin YL, Lin WW (2013) The tyrosine kinase Syk differentially regulates toll-like receptor signaling downstream of the adaptor molecules TRAF6 and TRAF3. Sci signal 6:ra71
Liu T, Gao YJ, Ji RR (2012) Emerging role of toll-like receptors in the control of pain and itch. Neuroscience bulletin 28:131–144
Lysakova-Devine T, Keogh B, Harrington B, Nagpal K, Halle A, Golenbock DT, Monie T, Bowie AG (2010) Viral inhibitory peptide of TLR4, a peptide derived from vaccinia protein A46, specifically inhibits TLR4 by directly targeting MyD88 adaptor-like and TRIF-related adaptor molecule. J Immunol 185:4261–4271
Madera-Salcedo IK, Cruz SL, Gonzalez-Espinosa C (2013) Morphine prevents lipopolysaccharide-induced TNF secretion in mast cells blocking IkappaB kinase activation and SNAP-23 phosphorylation: correlation with the formation of a beta-arrestin/TRAF6 complex. J Immunology 191:3400–3409
Nicotra L, Loram LC, Watkins LR, Hutchinson MR (2012) Toll-like receptors in chronic pain. Exp Neurol 234:316–329
Ohtori S, Takahashi K, Moriya H (2002) Inflammatory pain mediated by a phenotypic switch in brain-derived neurotrophic factor-immunoreactive dorsal root ganglion neurons innervating the lumbar facet joints in rats. Neurosci Lett 323:129–132
Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Arumugam TV (2009) Toll-like receptors in neurodegeneration. Brain Res Rev 59:278–292
Orita S, Miyagi M, Kobori S, Gemba T, Ishikawa T, Inoue G, Toyone T, Aoki Y, Eguchi Y, Takahashi K, Ohtori S (2013) IkappaB kinase beta inhibitor downregulates pain-related neuropeptide production in the sensory neurons innervating injured lumbar intervertebral discs in the dorsal root ganglia of rats. Spine J 13:284–288
Piao HZ, Choi IY, Park JS, Kim HS, Cheong JH, Son KH, Jeon SJ, Ko KH, Kim WK (2008) Wogonin inhibits microglial cell migration via suppression of nuclear factor-kappa B activity. Int Immunopharmacol 8:1658–1662
Saito O, Svensson CI, Buczynski MW, Wegner K, Hua XY, Codeluppi S, Schaloske RH, Deems RA, Dennis EA, Yaksh TL (2010) Spinal glial TLR4-mediated nociception and production of prostaglandin E(2) and TNF. Br J Pharmacol 160:1754–1764
Sakuma Y, Ohtori S, Miyagi M, Ishikawa T, Inoue G, Doya H, Koshi T, Ito T, Yamashita M, Yamauchi K, Suzuki M, Moriya H, Takahashi K (2007) Up-regulation of p55 TNF alpha-receptor in dorsal root ganglia neurons following lumbar facet joint injury in rats. Eur Spine J 16:1273–1278
Song X, Yao J, Wang F, Zhou M, Zhou Y, Wang H, Wei L, Zhao L, Li Z, Lu N, Guo Q (2013) Wogonin inhibits tumor angiogenesis via degradation of HIF-1alpha protein. Toxicol Appl Pharmacol 271:144–155
Stack J, Bowie AG (2012) Poxviral protein A46 antagonizes toll-like receptor 4 signaling by targeting BB loop motifs in toll-IL-1 receptor adaptor proteins to disrupt receptor: adaptor interactions. J Biol Chem 287:22672–22682
St-Jacques B, Ma W (2011) Role of prostaglandin E2 in the synthesis of the pro-inflammatory cytokine interleukin-6 in primary sensory neurons: an in vivo and in vitro study. J Neurochem 118:841–854
Stokes JA, Cheung J, Eddinger K, Corr M, Yaksh TL (2013) Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice. J Neuroinflammation 10:148
Tai MC, Tsang SY, Chang LY, Xue H (2005) Therapeutic potential of wogonin: a naturally occurring flavonoid. CNS Drug Rev 11:141–150
Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, Lathia JD, Siler DA, Chigurupati S, Ouyang X, Magnus T, Camandola S, Mattson MP (2007) Pivotal role for neuronal toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA 104:13798–13803
Tanga FY, Nutile-McMenemy N, DeLeo JA (2005) The CNS role of toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci USA 102:5856–5861
Tse KH, Chow KB, Leung WK, Wong YH, Wise H (2014) Lipopolysaccharide differentially modulates expression of cytokines and cyclooxygenases in dorsal root ganglion cells via toll-like receptor-4 dependent pathways. Neuroscience 267:241–251
Uceyler N, Tscharke A, Sommer C (2007) Early cytokine expression in mouse sciatic nerve after chronic constriction nerve injury depends on calpain. Brain Behav Immun 21:553–560
Wang F, Song X, Zhou M, Wei L, Dai Q, Li Z, Lu N, Guo Q (2013) Wogonin inhibits H2O2-induced vascular permeability through suppressing the phosphorylation of caveolin-1. Toxicology 305:10–19
Wang Z, Ren Z, Hu Z, Hu X, Zhang H, Wu H, Zhang M (2014) Angiotensin-II induces phosphorylation of ERK1/2 and promotes aortic adventitial fibroblasts differentiating into myofibroblasts during aortic dissection formation. J Mol Histol 45:401–412
Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24:450–455
Zang Y, He XH, Xin WJ, Pang RP, Wei XH, Zhou LJ, Li YY, Liu XG (2010) Inhibition of NF-kappaB prevents mechanical allodynia induced by spinal ventral root transection and suppresses the re-expression of Nav1.3 in DRG neurons in vivo and in vitro. Brain Res 1363:151–158
Zhou H, Yang HX, Yuan Y, Deng W, Zhang JY, Bian ZY, Zong J, Dai J, Tang QZ (2013) Paeoniflorin attenuates pressure overload-induced cardiac remodeling via inhibition of TGFbeta/Smads and NF-kappaB pathways. J Mol Histol 44:357–367
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Chen, S., Xiong, J., Zhan, Y. et al. Wogonin Inhibits LPS-Induced Inflammatory Responses in Rat Dorsal Root Ganglion Neurons Via Inhibiting TLR4–MyD88–TAK1-Mediated NF-κB and MAPK Signaling Pathway. Cell Mol Neurobiol 35, 523–531 (2015). https://doi.org/10.1007/s10571-014-0148-4
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DOI: https://doi.org/10.1007/s10571-014-0148-4