Advertisement

Neurochemical Research

, Volume 41, Issue 11, pp 3138–3146 | Cite as

Acetate Attenuates Lipopolysaccharide-Induced Nitric Oxide Production Through an Anti-Oxidative Mechanism in Cultured Primary Rat Astrocytes

  • Mitsuaki Moriyama
  • Ryosuke Kurebayashi
  • Kenji Kawabe
  • Katsura Takano
  • Yoichi Nakamura
Original Paper

Abstract

The biomolecule acetate can be utilized for energy production, lipid synthesis, and several metabolic processes. Acetate supplementation reduces neuroglial activation in a model of neuroinflammation induced by intraventricular injection of lipopolysaccharide (LPS). To investigate the mechanisms underlying the anti-inflammatory effect of acetate on glial cells, we examined the effect of acetate on nitric oxide (NO) production, which was experimentally activated by LPS, in cultured primary rat astrocytes. Acetate attenuated the LPS-induced NO production in a dose-dependent manner, although cell viability was not affected. Acetate suppressed the phosphorylation of p38-mitogen-activated protein kinase 24 h after LPS treatment. Acetate decreased the LPS-induced production of intracellular reactive oxygen species (ROS) at 4–24 h concomitant with an increase in glutathione. Acetate rescued astrocytes from the hydrogen peroxide-induced cell death by reducing ROS levels. These findings suggest that attenuation of NO production by acetate may alleviate glial cell damage during neuroinflammation. Acetate may offer a glioprotective effect through an anti-oxidative mechanism.

Keywords

Acetate Oxidative stress Neuroinflammation Glioprotection 

Abbreviations

DAN

2,3-Diaminonaphthalene

DCF

Dichlorofluorescein

DMEM

Dulbecco’s modified Eagle medium

FBS

Fetal bovine serum

GSH

Glutathione

H2DCFDA

2′,7′-Dichlorodihydrofluorescein diacetate

H2O2

Hydrogen peroxide

HBS

Hepes-buffered saline

iNOS

Inducible nitric oxide synthase

LPS

Lipopolysaccharide

MAPK

Mitogen-activated protein kinase

MTT

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-tetrazolium bromide

NFκB

Nuclear factor-kappaB

NO

Nitric oxide

Nrf2

NF-E2-related factor 2

PBS

Phosphate-buffered saline

ROS

Reactive oxygen species

Notes

Acknowledgments

This work was supported by a grant from the KIEIKAI Research Foundation (to M. M.) and by JSPS KAKENHI Grant numbers 26450447 (to M. M.) and 15 K07768 (to Y. N.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, Walters H, Tantawy MN, Fu A, Manning HC, Horton JD, Hammer RE, McKnight SL, Tu BP (2014) Acetate dependence of tumors. Cell 159:1591–1602. doi: 10.1016/j.cell.2014.11.020 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, Nemirovski A, Shen-Orr S, Laevsky I, Amit M, Bomze D, Elena-Herrmann B, Scherf T, Nissim-Rafinia M, Kempa S, Itskovitz-Eldor J, Meshorer E, Aberdam D, Nahmias Y (2015) Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab 21:392–402. doi: 10.1016/j.cmet.2015.02.002 CrossRefPubMedGoogle Scholar
  3. 3.
    Okabe S, Kodama Y, Cao H, Johannessen H, Zhao CM, Wang TC, Takahashi R, Chen D (2012) Topical application of acetic acid in cytoreduction of gastric cancer. A technical report using mouse model. J Gastroenterol Hepatol 27(Suppl 3):40–48. doi: 10.1111/j.1440-1746.2012.07070.x CrossRefPubMedGoogle Scholar
  4. 4.
    Long PM, Tighe SW, Driscoll HE, Fortner KA, Viapiano MS, Jaworski DM (2015) Acetate supplementation as a means of inducing glioblastoma stem-like cell growth arrest. J Cell Physiol 230:1929–1943. doi: 10.1002/jcp.24927 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32:1–14CrossRefPubMedGoogle Scholar
  6. 6.
    Correale J, Villa A (2009) Cellular elements of the blood–brain barrier. Neurochem Res 34:2067–2077. doi: 10.1007/s11064-009-0081-y CrossRefPubMedGoogle Scholar
  7. 7.
    Koehler RC, Gebremedhin D, Harder DR (2006) Role of astrocytes in cerebrovascular regulation. J Appl Physiol 100:307–317CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Rossi D, Volterra A (2009) Astrocytic dysfunction: insights on the role in neurodegeneration. Brain Res Bull 80:224–232. doi: 10.1016/j.brainresbull.2009.07.012 CrossRefPubMedGoogle Scholar
  9. 9.
    Ridet JL, Malhotra SK, Pivat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577CrossRefPubMedGoogle Scholar
  10. 10.
    Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647. doi: 10.1016/j.tins.2009.08.002 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Nomura Y (2001) NF-κB activation and IkBα dynamism involved in iNOS and chemokine induction in astroglial cells. Life Sci 68:1695–1701CrossRefPubMedGoogle Scholar
  12. 12.
    Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122:1164–1171. doi: 10.1172/JCI58644 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Saha RN, Pahan K (2006) Signals for the induction of nitric oxide synthase in astrocytes. Neurochem Int 49:154–163CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Calabrese V, Mamcuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8:766–775CrossRefPubMedGoogle Scholar
  15. 15.
    Murakami K, Nakamura Y, Yoneda Y (2003) Potentiation by ATP of lipopolysaccharide-stimulated nitric oxide production in cultured astrocytes. Neuroscience 117:37–42CrossRefPubMedGoogle Scholar
  16. 16.
    Sonnewald U, Kondziella D (2003) Neuronal glia interaction in different neurological diseases studied by ex vivo 13C NMR spectroscopy. NMR Biomed 16:424–429CrossRefPubMedGoogle Scholar
  17. 17.
    Waniewski RA, Martin DL (1998) Preferential utilization of acetate by astrocytes is attributable to transport. J Neurosci 18:5225–5233PubMedGoogle Scholar
  18. 18.
    Sonnewald U, Müller TB, Westergaard N, Unsgård G, Petersen SB, Schouboe A (1994) NMR spectroscopic study of cell cultures of astrocytes and neurons exposed to hypoxia: compartmentation of astrocyte metabolism. Neurochem Int 24:473–483CrossRefPubMedGoogle Scholar
  19. 19.
    Sailasuta N, Harris K, Tran T, Ross B (2011) Minimally invasive biomarker confirms glial activation present in Alzheimer’s disease: a preliminary study. Neuropsychiatr Dis Treat 7:495–499CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Marik J, Ogasawara A, Martin-McNulty B, Ross J, Flores JE, Gill HS, Tinianow JN, Vanderbilt AN, Nishimura M, Peale F, Pastuskovas C, Greve JM, van Bruggen N, Williams SP (2009) PET of glial metabolism using 2-18F fluoroacetate. J Nucl Med 50:982–990CrossRefPubMedGoogle Scholar
  21. 21.
    Reisenauer CJ, Bhatt DP, Mitteness DJ, Slanczka ER, Gienger HM, Watt JA, Rosenberger TA (2011) Acetate supplementation attenuates lipopolysaccharide-induced neuroinflammation. J Neurochem 117:264–274. doi: 10.1111/j.1471-4159.2011.07198.x CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Arun P, Ariyannur PS, Moffett JR, Xing G, Hamilton K, Grunberg NE, Ives JA, Namboodiri AM (2010) Matabolic acetate therapy for the treatment of traumatic brain injury. J Neurotrauma 27:293–298. doi: 10.1007/s10545-010-9100-z CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Freyer D, Weih M, Weber JR, Burger W, Scholz P, Manz R, Ziegenhorn A, Angestwurm K, Dirnagl U (1996) Pneumococcal cell wall components induce nitric oxide synthase and TNF-α in astroglial-enriched cultures. Glia 16:1–6CrossRefPubMedGoogle Scholar
  24. 24.
    Castano A, Herrera AJ, Cano J, Machado A (1998) Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system. J Neurochem 70:1584–1592CrossRefPubMedGoogle Scholar
  25. 25.
    Nakamura Y, Kitagawa T, Ihara H, Kozaki S, Moriyama M, Kannan Y (2006) Potentiation by high potassium of lipopolysaccharide-induced nitric oxide production from cultured astrocytes. Neurochem Int 48:43–49CrossRefPubMedGoogle Scholar
  26. 26.
    Takano K, Sugita K, Moriyama M, Hashida K, Hibino S, Choshi T, Murakami R, Yamada M, Suzuki H, Hori O, Nakamura Y (2011) A dibenzoylmethane derivative protects against hydrogen peroxide-induced cell death and inhibits lipopolysaccharide-induced nitric oxide production in cultured rat astrocytes. J Neurosci Res 89:955–965. doi: 10.1002/jnr.22617 CrossRefPubMedGoogle Scholar
  27. 27.
    Bhat NR, Feinstein DL, Shen Q, Bhat AN (2002) p38 MAPK-mediated transcriptional activation of inducible nitric-oxide synthase in glial cells. Roles of nuclear factors, nuclear factor kappa B, cAMP response element-binding protein, CCAAT/enhancer-binding protein-beta, and activating transcription factor-2. J Biol Chem 277:29584–29592CrossRefPubMedGoogle Scholar
  28. 28.
    Gorina R, Font-Nieves M, Márquez-Kisinousky L, Santalucia T, Planas AM (2011) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFκB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59:242–255. doi: 10.1002/glia.21094 CrossRefPubMedGoogle Scholar
  29. 29.
    Lee SY, Son DJ, Lee YK, Lee JW, Lee HJ, Yun YW, Ha TY, Hong JT (2006) Inhibitory effect of sesaminol glucosides on lipopolysaccharide-induced NF-κB activation and target gene expression in cultured rat astrocytes. Neurosci Res 56:204–212CrossRefPubMedGoogle Scholar
  30. 30.
    Pawate S, Shen Q, Fan F, Bhat NR (2004) Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. J Neurosci Res 77:540–551CrossRefPubMedGoogle Scholar
  31. 31.
    Dringen R, Gutterer JM, Hirrlinger J (2000) Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem 267:4912–4916CrossRefPubMedGoogle Scholar
  32. 32.
    Czaja MJ, Liu H, Wang Y (2003) Oxidant-induced hepatocyte injury from menadione is regulated by ERK and AP-1 signaling. Hepatology 37:1405–1413CrossRefPubMedGoogle Scholar
  33. 33.
    Remacle J, Raes M, Toussaint O, Renard P, Rao G (1995) Low levels of reactive oxygen species as modulators of cell function. Mutat Res 316:103–122CrossRefPubMedGoogle Scholar
  34. 34.
    Suzuki YJ, Forman HJ, Sevanian A (1997) Oxidants as stimulators of signal transduction. Free Radic Biol Med 22:269–285CrossRefPubMedGoogle Scholar
  35. 35.
    Moriyama M, Jayakumar AR, Tong XY, Norenberg MD (2010) Role of mitogen-activated protein kinases in the mechanism of oxidant-induced cell swelling in cultured astrocytes. J Neurosci Res 88:2450–2458. doi: 10.1002/jnr.22400 PubMedGoogle Scholar
  36. 36.
    Hsieh HL, Yang CM (2013) Role of redox signaling in neuroinflammation and neurodegenerative diseases. Biomed Res Int 2013:484613. doi: 10.1155/2013/484613.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB (2014) Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20:1126–1167. doi: 10.1089/ars.2012.5149 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ozden O, Park SH, Kim HS, Jiang H, Coleman MC, Spitz DR, Gius D (2011) Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. Aging 3:102–107CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23:3394–3406PubMedGoogle Scholar
  40. 40.
    Vargas MR, Pehar M, Cassina P, Beckman JS, Barbeito L (2006) Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. J Neurochem 97:687–696CrossRefPubMedGoogle Scholar
  41. 41.
    Sun Z, Chin YE, Zhang DD (2009) Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response. Mol Cell Biol 29:2658–2672. doi: 10.1128/MCB.01639-08 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Bhat NR, Zhang P, Lee JC, Hogan EL (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor a gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18:1633–1641PubMedGoogle Scholar
  43. 43.
    Dickinson RJ, Keyse SM (2006) Diverse physiological functions for dual-specificity MAP kinase phosphatases. J Cell Sci 119:4607–4615CrossRefPubMedGoogle Scholar
  44. 44.
    Owens DM, Keyse SM (2007) Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26:3203–3213CrossRefPubMedGoogle Scholar
  45. 45.
    Cao W, Bao C, Padalko E, Lowenstein CJ (2008) Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. J Exp Med 205:1491–1503. doi: 10.1084/jem.20071728 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Chi H, Flavell RA (2008) Acetylation of MKP-1 and the control of inflammation. Sci Signal 1(41):e44. doi: 10.1126/scisignal.141pe44 CrossRefGoogle Scholar
  47. 47.
    Soliman ML, Combs CK, Rosenberger TA (2013) Modulation of inflammatory cytokines and mitogen-activated protein kinases by acetate in primary astrocytes. J Neuroimmne Pharmacol 8:287–300. doi: 10.1007/s11481-012-9426-4 CrossRefGoogle Scholar
  48. 48.
    Zhang B, West EJ, Van KC, Gurkoff GG, Zhou J, Zhang XM, Kozikowski AP, Lyeth BG (2008) HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Res 1226:181–191. doi: 10.1016/j.brainres.2008.05.085 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ji W, Hong L, Zhang M, Zhang W (2012) Neuroprotective effects of valproic acid following transient global ischemia in rats. Life Sci 90:463–468. doi: 10.1016/j.lfs.2012.01.001 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Laboratory of Integrative Physiology in Veterinary SciencesOsaka Prefecture UniversityIzumisanoJapan

Personalised recommendations