Skip to main content
SpringerLink
Log in

Indoline derivatives mitigate liver damage in a mouse model of acute liver injury

  • Original article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Exposure of mice to D-galactosamine (GalN) and lipopolysaccharide (LPS) induces acute liver failure through elevation of TNF-α, which causes liver damage resembling that in humans. The current study evaluated in this model the effect of two indoline derivatives, which have anti-inflammatory activity in macrophages.

Methods

AN1297 and AN1284 (0.025–0.75 mg/kg) or dexamethasone (3 mg/kg), were injected subcutaneously, 15 min before intraperitoneal injection of GalN (800 mg) plus LPS (50 μg) in male Balb/C mice. After 6 h, their livers were evaluated histologically by staining with hematoxylin and eosin for tissue damage and by cleaved caspase 3 for apoptosis. Activity of liver enzymes, alanine transaminase (ALT) and aspartate aminotransferase (AST) and levels of TNF-α and IL-6 were measured in plasma, and those of TNF-α and IL-6, in the liver.

Results

AN1297 (0.075–0.75 mg/kg) and AN1284 (0.25–0.75 mg/kg) maximally reduced ALT by 51% and 80%, respectively. Only AN1284 (0.25 and 0.75 mg/kg) reduced AST by 41% and 48%. AN1297 and AN1284 (0.25 mg/kg) decreased activation of caspase 3 (a sign of apoptosis) by 80% and plasma TNF-α by 75%. AN1297 and AN1284 (0.075 mg/kg) prevented the rise in TNF-α and IL-6 in the liver. AN1284 (0.25 mg/kg) reduced mortality from 90% to 20% (p < 0.01) and AN1297, to 60% (p = 0.121). Both indoline derivatives inhibited the phosphorylation of MAPK p38 and DNA binding of the transcription factor, AP-1.

Conclusion

While both compounds are highly potent anti-inflammatory agents, AN1284 is more effective in mitigating the underlying causes of GalN/LPS-induced acute liver failure in mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010;376:190–201.

    Article  Google Scholar 

  2. Khashab M, Tector AJ, Kwo PY. Epidemiology of acute liver failure. Curr Gastroenterol Rep 2007;9:66–73.

    Article  Google Scholar 

  3. Lee WM. Etiologies of acute liver failure. Semin Liver Dis 2008;28:142–52.

    Article  Google Scholar 

  4. O’Grady JG. Acute liver failure. Postgrad Med J 2005;81:148–54.

    Article  Google Scholar 

  5. Rahman TM, Hodgson HJ. Animal models of acute hepatic failure. Int J Exp Pathol 2000;81:145–57.

    Article  CAS  Google Scholar 

  6. Tunon MJ, Alvarez M, Culebras JM, Gonzalez-Gallego J. An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure. World J Gastroenterol 2009;15:3086–98.

    Article  CAS  Google Scholar 

  7. Maes M, Vinken M, Jaeschke H. Experimental models of hepatotoxicity related to acute liver failure. Toxicol Appl Pharmacol 2016;290:86–97.

    Article  CAS  Google Scholar 

  8. Zhan Y, Wang Z, Yang P, Wang T, Xia L, Zhou M, et al. Adenosine 5’-monophosphate ameliorates D-galactosamine/lipopolysaccharide-induced liver injury through an adenosine receptor-independent mechanism in mice. Cell Death Dis 2014;5:e985.

    Article  CAS  Google Scholar 

  9. Ben-Ari Z, Zilbermints V, Pappo O, Avlas O, Sharon E, Greif F, et al. Erythropoietin increases survival and attenuates fulminant hepatic failure injury induced by D-galactosamine/lipopolysaccharide in mice. Transplantation 2011;92:18–24.

    Article  CAS  Google Scholar 

  10. Freudenberg MA, Galanos C. Tumor necrosis factor alpha mediates lethal activity of killed gram-negative and gram-positive bacteria in D-galactosamine-treated mice. Infect Immun 1991;59:2110–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Streetz K, Leifeld L, Grundmann D, Ramakers J, Eckert K, Spengler U, et al. Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure. Gastroenterology 2000;119:446–60.

    Article  CAS  Google Scholar 

  12. Li X, Gou C, Yang H, Qiu J, Gu T, Wen T. Echinacoside ameliorates D-galactosamine plus lipopolysaccharide-induced acute liver injury in mice via inhibition of apoptosis and inflammation. Scand J Gastroenterol 2014;49:993–1000.

    Article  CAS  Google Scholar 

  13. Lian LH, Jin X, Wu YL, Cai XF, Lee JJ, Nan JX. Hepatoprotective effects of Sedum sarmentosum on D-galactosamine/lipopolysaccharide-induced murine fulminant hepatic failure. J Pharmacol Sci 2010;114:147–57.

    Article  CAS  Google Scholar 

  14. Finkin-Groner E, Moradov D, Shifrin H, Bejar C, Nudelman A, Weinstock M. Indoline-3-propionate and 3-aminopropyl carbamates reduce lung injury and pro-inflammatory cytokines induced in mice by LPS. Br J Pharmacol 2015;172:1101–13.

    Article  CAS  Google Scholar 

  15. Shifrin H, Moradov D, Bejar C, Schorer-Apelbaum D, Weinstock M. Novel indoline derivatives prevent inflammation and ulceration in dinitro-benzene sulfonic acid-induced colitis in rats. Pharmacol Rep 2016;68:1312–8.

    Article  CAS  Google Scholar 

  16. Miceli PC, Jacobson K. Cholinergic pathways modulate experimental dinitrobenzene sulfonic acid colitis in rats. Auton Neurosci 2003;105:16–24.

    Article  CAS  Google Scholar 

  17. Shifrin H, Nadler-Milbauer M, Shoham S, Weinstock M. Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses. PLoS One 2013;8:e57668.

    Article  CAS  Google Scholar 

  18. Duan WR, Garner DS, Williams SD, Funckes-Shippy CL, Spath IS, Blomme EA. Comparison of immunohistochemistry for activated caspase-3 and cleaved cytokeratin 18 with the TUNEL method for quantification of apoptosis in histological sections of PC-3 subcutaneous xenografts. J Pathol 2003;199:221–8.

    Article  CAS  Google Scholar 

  19. Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R. In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 1995;21:1465–8.

    CAS  PubMed  Google Scholar 

  20. Das J, Ghosh J, Manna P, Sil PC. Protective role of taurine against arsenic-induced mitochondria-dependent hepatic apoptosis via the inhibition of PKCdelta-JNK pathway. PLoS One 2010;5:e12602.

    Article  Google Scholar 

  21. Leist M, Gantner F, Bohlinger I, Tiegs G, Germann PG, Wendel A. Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. Am J Pathol 1995;146:1220–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang CC, Cheng PY, Peng YJ, Wu ES, Wei HP, Yen MH. Naltrexone protects against lipopolysaccharide/D-galactosamine-induced hepatitis in mice. J Pharmacol Sci 2008;108:239–47.

    Article  CAS  Google Scholar 

  23. Gong X, Luo FL, Zhang L, Li HZ, Wu MJ, Li XH, et al. Tetrandrine attenuates lipopolysaccharide-induced fulminant hepatic failure in D-galactosamine-sensitized mice. Int Immunopharmacol 2010;10:357–63.

    Article  CAS  Google Scholar 

  24. Gao YZ, Zhao LF, Ma J, Xue WH, Zhao H. Protective mechanisms of wogonoside against lipopolysaccharide/D-galactosamine-induced acute liver injury in mice. Eur J Pharmacol 2016;780:8–15.

    Article  CAS  Google Scholar 

  25. Pan CW, Zhou GY, Chen WL, Zhuge L, Jin LX, Zheng Y, et al. Protective effect of forsythiaside A on lipopolysaccharide/d-galactosamine-induced liver injury. Int Immunopharmacol 2015;26:80–5.

    Article  CAS  Google Scholar 

  26. Tomar S, Nagarkatti M, Nagarkatti PS. 3,3′-Diindolylmethane attenuates LPS-mediated acute liver failure by regulating miRNAs to target IRAK4 and suppress Toll-like receptor signalling. Br J Pharmacol 2015;172:2133–47.

    Article  CAS  Google Scholar 

  27. Tomar S, Zumbrun EE, Nagarkatti M, Nagarkatti PS. Protective role of cannabinoid receptor 2 activation in galactosamine/lipopolysaccharide-induced acute liver failure through regulation of macrophage polarization and microRNAs. J Pharmacol Exp Ther 2015;353:369–79.

    Article  CAS  Google Scholar 

  28. Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002;298:1911–2.

    Article  CAS  Google Scholar 

  29. Liu Y, Shepherd EG, Nelin LD. MAPK phosphatases-regulating the immune response. Nat Rev Immunol 2007;7:202–12.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel

    Efrat Finkin-Groner & Marta Weinstock

  2. Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, The Hebrew University of Jerusalem, Jerusalem, Israel

    Shlomi Finkin

  3. Department of Chemistry, Bar Ilan University, Ramat Gan, Israel

    Shani Zeeli

Authors
  1. Efrat Finkin-Groner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shlomi Finkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shani Zeeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marta Weinstock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marta Weinstock.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Finkin-Groner, E., Finkin, S., Zeeli, S. et al. Indoline derivatives mitigate liver damage in a mouse model of acute liver injury. Pharmacol. Rep 69, 894–902 (2017). https://doi.org/10.1016/j.pharep.2017.03.025

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2017.03.025

Keywords

Search

Navigation