Archives of Pharmacal Research

, Volume 42, Issue 8, pp 695–703 | Cite as

Hesperetin inhibits neuroinflammation on microglia by suppressing inflammatory cytokines and MAPK pathways

  • Sun Hyo Jo
  • Mi Eun Kim
  • Jun Hwi Cho
  • Yujeong Lee
  • Jaewon Lee
  • Yong-Duk Park
  • Jun Sik LeeEmail author
Research Article


Neuroinflammation is a specific or nonspecific immunological reaction in the central nervous system that is induced by microglia activation. Appropriate regulation of activated microglial cells is therefore important for inhibiting neuroinflammation. Hesperetin is a natural flavanone and an aglycone of hesperidin that is found in citrus fruits. Hesperetin reportedly possesses anti-inflammatory, anti-cancer, and antioxidant effects. However, the anti-neuroinflammatory effects of hesperetin on microglia are still unknown. Here, we investigated the anti-neuroinflammatory effects of hesperetin on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. We found that hesperetin strongly inhibited nitric oxide production and expression of inducible nitric oxide synthase in LPS-stimulated BV-2 microglial cells. Hesperetin also significantly reduced secretion of inflammatory cytokines including interleukin (IL)-1β and IL-6. Furthermore, hesperetin down-regulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase, exerting anti-inflammatory effects. Hesperetin suppressed astrocyte and microglia activation in the LPS-challenged mouse brain. Collectively, our findings indicate that hesperetin inhibits microglia-mediated neuroinflammation and could be a prophylactic treatment for neurodegenerative diseases.


Hesperetin Neuroinflammation Inflammatory cytokines IL-1 IL-6 MAPK Microglia 


Compliance with ethical standards

Conflicts of interest

The authors declare no conflict of interest.


  1. Al Rahim M, Nakajima A, Misawa N, Shindo K, Adachi K, Shizuri Y, Ohizumi Y, Yamakuni T (2008) A novel diol-derivative of chalcone produced by bioconversion, 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, activates PKA/MEK/ERK signaling and antagonizes A beta-inhibition of the cascade in cultured rat CNS neurons. Eur J Pharmacol 600:10–17CrossRefGoogle Scholar
  2. Ding F, Li F, Li Y, Hou X, Ma Y, Zhang N, Ma J, Zhang R, Lang B, Wang H, Wang Y (2016) HSP60 mediates the neuroprotective effects of curcumin by suppressing microglial activation. Exp Ther Med 12:823–828CrossRefGoogle Scholar
  3. Gan P, Zhang L, Chen Y, Zhang Y, Zhang F, Zhou X, Zhang X, Gao B, Zhen X, Zhang J, Zheng LT (2015) Anti-inflammatory effects of glaucocalyxin B in microglia cells. J Pharmacol Sci 128:35–46CrossRefGoogle Scholar
  4. Jahn H (2013) Memory loss in Alzheimer’s disease. Dialogues Clin Neurosci 15:445–454Google Scholar
  5. Kheradmand E, Hajizadeh Moghaddam A, Zare M (2018) Neuroprotective effect of hesperetin and nano-hesperetin on recognition memory impairment and the elevated oxygen stress in rat model of Alzheimer’s disease. Biomed Pharmacother 97:1096–1101CrossRefGoogle Scholar
  6. Kim GD (2014) Hesperetin inhibits vascular formation by suppressing of the PI3 K/AKT, ERK, and p38 MAPK signaling pathways. Prev Nutr Food Sci 19:299–306CrossRefGoogle Scholar
  7. Mairuae N, Cheepsunthorn P (2018) Valproic acid attenuates nitric oxide and interleukin-1beta production in lipopolysaccharide-stimulated iron-rich microglia. Biomed Rep 8:359–364Google Scholar
  8. Mcgeer P, Itagaki S, Boyes B, Mcgeer E (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285CrossRefGoogle Scholar
  9. Mecocci P, Boccardi V, Cecchetti R, Bastiani P, Scamosci M, Ruggiero C, Baroni M (2018) A long journey into aging, brain aging, and Alzheimer’s disease following the oxidative stress tracks. J Alzheimers Dis 62:1319–1335CrossRefGoogle Scholar
  10. Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374:647–650CrossRefGoogle Scholar
  11. Parhiz H, Roohbakhsh A, Soltani F, Rezaee R, Iranshahi M (2015) Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res 29:323–331CrossRefGoogle Scholar
  12. Pennisi M, Crupi R, Di Paola R, Ontario ML, Bella R, Calabrese EJ, Crea R, Cuzzocrea S, Calabrese V (2017) Inflammasomes, hormesis, and antioxidants in neuroinflammation: role of NRLP3 in Alzheimer disease. J Neurosci Res 95:1360–1372CrossRefGoogle Scholar
  13. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462CrossRefGoogle Scholar
  14. Reale M, Brenner T, Greig NH, Inestrosa N, Paleacu D (2010) Neuroinflammation, AD, and Dementia. Int J Alzheimers Dis. Google Scholar
  15. Sapp E, Kegel K, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, Bhide P, Vonsattel J, Difiglia M (2001) Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol 60:161–172CrossRefGoogle Scholar
  16. Schetters STT, Gomez-Nicola D, Garcia-Vallejo JJ, Van Kooyk Y (2017) Neuroinflammation: microglia and T cells get ready to Tango. Front Immunol 8:1905CrossRefGoogle Scholar
  17. Shirzad M, Heidarian E, Beshkar P, Gholami-Arjenaki M (2017) Biological effects of Hesperetin on Interleukin-6/Phosphorylated Signal transducer and activator of transcription 3 pathway signaling in prostate cancer PC3 cells. Pharmacogn Res 9:188–194Google Scholar
  18. Smina TP, Mohan A, Ayyappa KA, Sethuraman S, Krishnan UM (2015) Hesperetin exerts apoptotic effect on A431 skin carcinoma cells by regulating mitogen activated protein kinases and cyclins. Cell Mol Biol (Noisy-le-grand) 61:92–99Google Scholar
  19. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647CrossRefGoogle Scholar
  20. Teismann P, Schulz JB (2004) Cellular pathology of Parkinson’s disease: astrocytes, microglia and inflammation. Cell Tissue Res 318:149–161CrossRefGoogle Scholar
  21. Teismann P, Tieu K, Cohen O, Choi DK, Wu DC, Marks D, Vila M, Jackson-Lewis V, Przedborski S (2003) Pathogenic role of glial cells in Parkinson’s disease. Mov Disord 18:121–129CrossRefGoogle Scholar
  22. Tiwari PC, Pal R (2017) The potential role of neuroinflammation and transcription factors in Parkinson disease. Dialogues Clin Neurosci 19:71–80Google Scholar
  23. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57:67–81CrossRefGoogle Scholar
  24. Xu H, Qin W, Hu X, Mu S, Zhu J, Lu W, Luo Y (2018) Lentivirus-mediated overexpression of OTULIN ameliorates microglia activation and neuroinflammation by depressing the activation of the NF-kappaB signaling pathway in cerebral ischemia/reperfusion rats. J Neuroinflamm 15:83CrossRefGoogle Scholar
  25. Ye L, Chan FL, Chen S, Leung LK (2012) The citrus flavonone hesperetin inhibits growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice. J Nutr Biochem 23:1230–1237CrossRefGoogle Scholar
  26. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong J-S (2005) Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19:533–542CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Department of Life Science, Immunology Research Lab, BK21-plus Research Team for Bioactive Control Technology, College of Natural SciencesChosun UniversityGwangjuRepublic of Korea
  2. 2.Department of Pharmacy, College of Pharmacy, Molecular Inflammation Research Center for Aging InterventionPusan National UniversityBusanRepublic of Korea
  3. 3.Department of Preventive and Society Dentistry, School of Dentistry, Djkunghee HospitalKyung Hee UniversitySeoulRepublic of Korea

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