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Neuroprotective and anti-inflammatory effects of isoliquiritigenin in kainic acid-induced epileptic rats via the TLR4/MYD88 signaling pathway

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Abstract

Epileptogenesis is a complex pathological process that occurs after an initial brain injury and involves a series of molecular events. Isoliquiritigenin (ISL), a flavonoid in licorice, is reported to have anti-inflammatory and antioxidant effects in various experimental models, but its specific roles and molecular mechanisms in the epileptogenic process following kainic acid (KA) treatment remain unclear. The purpose of this study was to explore the effects of ISL pretreatment in KA-induced epileptic rats and the underlying mechanisms. Our findings show that ISL pretreatment significantly attenuated the KA-induced expression of ionized calcium‐binding adapter molecule 1 (IBα1)-labeled microglia (F(3, 20) = 97.29, p < 0.01, ηp2 = 0.94) and glial fibrillary acidic protein (GFAP)-positive astrocytes (F(3, 20) = 72.48, p < 0.01, ηp2 = 0.92), and the release of inflammatory mediators, such as TNF-α (F(3, 20) = 133.14, p < 0.01, ηp2 = 0.95), IL-1β, and C–C motif chemokine ligand 3 (CCL3). ISL pretreatment given before KA also significantly prevented apoptotic neuronal injury by upregulating the activities of superoxide dismutase and glutathione peroxidase. It also significantly suppressed the protein levels of Toll-like receptor 4 (TLR4) (F(3, 20) = 63.23, p < 0.01, ηp2 = 0.91) and its downstream molecules, myeloid differentiation primary response 88 (MYD88), phosphorylated (p-)IκBα, and p-NF-κB. Blocking TLR4/MYD88 signaling also attenuated KA-induced neuroinflammation and neuronal damage in the hippocampus. Overall, our study demonstrates that ISL pretreatment plays neuroprotective and anti-inflammatory roles in KA-induced epileptogenesis, which may be mediated by the TLR4/MYD88 signaling pathway.

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References

  • Candelario-Jalil E, Al-Dalain SM, Castillo R, Martínez G, Fernández OS (2001) Selective vulnerability to kainate-induced oxidative damage in different rat brain regions. J Appl Toxicol 21:403–407

    Article  CAS  Google Scholar 

  • Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I (2007) Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 115:1599–1608

    Article  CAS  Google Scholar 

  • Chu K, Jung KH, Lee ST, Kim JH, Kang KM, Kim HK, Lim JS, Park HK, Kim M, Lee SK, Roh JK (2008) Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia 49:1723–1732

    Article  CAS  Google Scholar 

  • Du F, Gesang Q, Cao J, Qian M, Ma L, Wu D, Yu H (2016) Isoliquiritigenin attenuates atherogenesis in apolipoprotein E-deficient mice. Int J Mol Sci 17:1932

    Article  Google Scholar 

  • Funakoshi-Tago M, Ohsawa K, Ishikawa T, Nakamura F, Ueda F, Narukawa Y, Kiuchi F, Tamura H, Tago K, Kasahara T (2016) Inhibitory effects of flavonoids extracted from Nepalese propolis on the LPS signaling pathway. Int Immunopharmacol 40:550–560

    Article  CAS  Google Scholar 

  • Honda H, Nagai Y, Matsunaga T, Saitoh S, Akashi-Takamura S, Hayashi H, Fujii I, Miyake K, Muraguchi A, Takatsu K (2012) Glycyrrhizin and isoliquiritigenin suppress the LPS sensor toll-like receptor 4/MD-2 complex signaling in a different manner. J Leukoc Biol 91:967–976

    Article  CAS  Google Scholar 

  • Jeon JP, Buono RJ, Han BG, Jang EY, Kim SC, Yang CH, Hwang M (2008) Proteomic and behavioral analysis of response to isoliquiritigenin in brains of acute cocaine treated rats. J Proteome Res 7:5094–5102

    Article  CAS  Google Scholar 

  • Korff CM, Dale RC (2017) The immune system in pediatric seizures and epilepsies. Pediatrics 140:e20163534

    Article  Google Scholar 

  • Larochelle A, Bellavance MA, Rivest S (2015) Role of adaptor protein MyD88 in TLR-mediated preconditioning and neuroprotection after acute excitotoxicity. Brain Behav Immun 46:221–231

    Article  CAS  Google Scholar 

  • Lee MJ, Yang CH, Jeon JP, Hwang M (2009) Protective effects of isoliquiritigenin against methamphetamine-induced neurotoxicity in mice. J Pharmacol Sci 111:216–220

    Article  CAS  Google Scholar 

  • Lee SH, Kim JY, Seo GS, Kim YC, Sohn DH (2009) Isoliquiritigenin, from Dalbergia odorifera, up-regulates anti-inflammatory heme oxygenase-1 expression in RAW264.7 macrophages. Inflamm Res 58:257–262

    Article  CAS  Google Scholar 

  • Lee HK, Yang EJ, Kim JY, Song KS, Seong YH (2012) Inhibitory effects of glycyrrhizae radix and its active component, isoliquiritigenin, on Aβ (25–35)-induced neurotoxicity in cultured rat cortical neurons. Arch Pharm Res 35:897–904

    Article  CAS  Google Scholar 

  • Li Z, Li B, Zhu X, Yin P, Liu J, Huang S, Sun R (2013) Neuroprotective effects of anti-high-mobility group box 1 antibody in juvenile rat hippocampus after kainic acid-induced status epilepticus. Neuroreport 24:785–790

    Article  CAS  Google Scholar 

  • Ma X, Fang F, Song M, Ma S (2015) The effect of isoliquiritigenin on learning and memory impairments induced by high-fat diet via inhibiting TNF-α/JNK/IRS signaling. Biochem Biophys Res Commun 464:1090–1095

    Article  CAS  Google Scholar 

  • Mogami S, Sadakane C, Nahata M, Mizuhara Y, Yamada C, Hattori T, Takeda H (2016) CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia. Sci Rep 6:27516

    Article  CAS  Google Scholar 

  • Park SJ, Song HY, Youn HS (2009) Suppression of the TRIF-dependent signaling pathway of toll-like receptors by isoliquiritigenin in RAW264.7 macrophages. Mol Cells 28:365–368

    Article  Google Scholar 

  • Park SJ, Youn HS (2010) Suppression of homodimerization of toll-like receptor 4 by isoliquiritigenin. Phytochemistry 71:1736–1740

    Article  CAS  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Elsevier Academic Press, Burlington

    Google Scholar 

  • Peng F, Du Q, Peng C, Wang N, Tang H, Xie X, Shen J, Chen J (2015) A review: the pharmacology of isoliquiritigenin. Phytother Res 29:969–977

    Article  CAS  Google Scholar 

  • Qi M, Zheng L, Qi Y, Han X, Xu Y, Xu L, Yin L, Wang C, Zhao Y, Sun H, Liu K, Peng J (2015) Dioscin attenuates renal ischemia/reperfusion injury by inhibiting the TLR4/MyD88 signaling pathway via up-regulation of HSP70. Pharmacol Res 100:341–352

    Article  CAS  Google Scholar 

  • Rahimifard M, Maqbool F, Moeini-Nodeh S, Niaz K, Abdollahi M, Braidy N, Nabavi SM, Nabavi SF (2017) Targeting the TLR4 signaling pathway by polyphenols: a novel therapeutic strategy for neuroinflammation. Ageing Res Rev 36:11–19

    Article  CAS  Google Scholar 

  • Rakhade SN, Jensen FE (2009) Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol 5:380–391

    Article  CAS  Google Scholar 

  • Rizzi M, Perego C, Aliprandi M, Richichi C, Ravizza T, Colella D, Velískŏvá J, Moshé SL, De Simoni MG, Vezzani A (2003) Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development. Neurobiol Dis 14:494–503

    Article  CAS  Google Scholar 

  • Shin EJ, Ko KH, Kim WK, Chae JS, Yen TP, Kim HJ, Wie MB, Kim HC (2008) Role of glutathione peroxidase in the ontogeny of hippocampal oxidative stress and kainate seizure sensitivity in the genetically epilepsy-prone rats. Neurochem Int 52:1134–1147

    Article  CAS  Google Scholar 

  • Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376

    Article  CAS  Google Scholar 

  • Thiyagarajan P, Chandrasekaran CV, Deepak HB, Agarwal A (2011) Modulation of lipopolysaccharide-induced pro-inflammatory mediators by an extract of Glycyrrhiza glabra and its phytoconstituents. Inflammopharmacology 19:235–241

    Article  CAS  Google Scholar 

  • Vezzani A, Granata T (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46:1724–1743

    Article  CAS  Google Scholar 

  • Wang N, Han X, Liu H, Zhao T, Li J, Feng Y, Mi X, Zhang Y, Chen Y, Wang X (2017) Myeloid differentiation factor 88 is up-regulated in epileptic brain and contributes to experimental seizures in rats. Exp Neurol 295:23–35

    Article  CAS  Google Scholar 

  • Watanabe Y, Nagai Y, Honda H, Okamoto N, Yamamoto S, Hamashima T, Ishii Y, Tanaka M, Suganami T, Sasahara M, Miyake K, Takatsu K (2016) Isoliquiritigenin attenuates adipose tissue inflammation in vitro and adipose tissue fibrosis through inhibition of innate immune responses in mice. Sci Rep 6:23097

    Article  CAS  Google Scholar 

  • Yang EJ, Min JS, Ku HY, Choi HS, Park MK, Kim MK, Song KS, Lee DS (2012) Isoliquiritigenin isolated from Glycyrrhiza uralensis protects neuronal cells against glutamate-induced mitochondrial dysfunction. Biochem Biophys Res Commun 421:658–664

    Article  CAS  Google Scholar 

  • Zeng J, Chen Y, Ding R, Feng L, Fu Z, Yang S, Deng X, Xie Z, Zheng S (2017) Isoliquiritigenin alleviates early brain injury after experimental intracerebral hemorrhage via suppressing ROS- and/or NF-κB-mediated NLRP3 inflammasome activation by promoting Nrf2 antioxidant pathway. J Neuroinflammation 14:119

    Article  Google Scholar 

  • Zhan C, Yang J (2006) Protective effects of isoliquiritigenin in transient middle cerebral artery occlusion-induced focal cerebral ischemia in rats. Pharmacol Res 53:303–309

    Article  CAS  Google Scholar 

  • Zhang F, Dong H, Lv T, Jin K, Jin Y, Zhang X, Jiang J (2018) Moderate hypothermia inhibits microglial activation after traumatic brain injury by modulating autophagy/apoptosis and the MyD88-dependent TLR4 signaling pathway. J Neuroinflammation 15:273

    Article  Google Scholar 

  • Zhu XB, Wang YB, Chen O, Zhang DQ, Zhang ZH, Cao AH, Huang SY, Sun RP (2012) Characterization of the expression of macrophage inflammatory protein-1α (MIP-1α) and C-C chemokine receptor 5 (CCR34) after kainic acid-induced status epilepticus (SE) in juvenile rats. Neuropathol Appl Neurobiol 38:602–616

    Article  CAS  Google Scholar 

  • Zou P, Ji HM, Zhao JW, Ding XM, Zhen ZG, Zhang X, Nie XQ, Xue LX (2018) Protective effect of isoliquiritigenin against cerebral injury in septic mice via attenuation of NF-κB. Inflammopharmacology. https://doi.org/10.1007/s10787-018-0503-z

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was funded by the Basic Research for Natural Science Project of Shandong University (No. 2015TS014) and China Scholarship Council (201706225013). We also thank International Science Editing (https://www.internationalscienceediting.com) for editing this manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, The Second Hospital of Shandong University, Jinan, 250012, China

    Xiaobo Zhu, Ou Chen, Jiang Xue & Yibiao Wang

  2. Department of Ophthalmology, The Second People’s Hospital of Jinan City, Jinan, 250000, China

    Jiankun Liu

  3. Nursing School, Shandong University, Jinan, 250012, China

    Ou Chen

  4. The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University, Jinan, 250012, China

    Shanying Huang

  5. Department of Pediatrics, Jinan Central Hospital Affiliated To Shandong University, Jinan, 250000, China

    Weiwei Zhu

  6. Department of Pediatrics, The Second Hospital of Shandong University, No. 247 Beiyuan Street, Jinan, 250033, China

    Weiwei Zhu & Yibiao Wang

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  1. Xiaobo Zhu
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Zhu, X., Liu, J., Chen, O. et al. Neuroprotective and anti-inflammatory effects of isoliquiritigenin in kainic acid-induced epileptic rats via the TLR4/MYD88 signaling pathway. Inflammopharmacol 27, 1143–1153 (2019). https://doi.org/10.1007/s10787-019-00592-7

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