Withaferin-A Reduces Acetaminophen-Induced Liver Injury in Mice

Ravirajsinh N. Jadeja, Nathalie H. Urrunaga, Suchismita Dash, Sandeep Khurana, Neeraj Kumar Saxena

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Withaferin-A (WA) has anti-oxidant activities however, its therapeutic potential in acetaminophen (APAP) hepatotoxicity is unknown. We performed a proof-of-concept study to assess the therapeutic potential of WA in a mouse model that mimics APAP-induced liver injury (AILI) in humans. Overnight fasted C57BL/6NTac (5-6 wk. old) male mice received 200 mg/kg APAP intraperitoneally (i.p.). After 1 h mice were treated with 40 mg/kg WA or vehicle i.p., and euthanized 4 and 16 h later; their livers were harvested and serum collected for analysis. At 4 h, compared to vehicle-treated mice, WA-treated mice had reduced serum ALT levels, hepatocyte necrosis and intrahepatic hemorrhage. All APAP-treated mice had reduced hepatic glutathione (GSH) levels however, reduction in GSH was lower in WA-treated when compared to vehicle-treated mice. Compared to vehicle-treated mice, livers from WA-treated mice had reduced APAP-induced JNK activation, mitochondrial Bax translocation, and nitrotyrosine generation. Compared to vehicle-treated mice, WA-treated mice had increased hepatic up-regulation of Nrf2, Gclc and Nqo1, and down-regulation of Il-6 and Il-1β. The hepatoprotective effect of WA persisted at 16 h. Compared to vehicle-treated mice, WA-treated mice had reduced hepatocyte necrosis and hepatic expression of Il-6, Tnf-α and Il-1β, increased hepatic Gclc and Nqo1 expression and GSH levels, and reduced lipid peroxidation. Finally, in AML12 hepatocytes, WA reduced H2O2-induced oxidative stress and necrosis by preventing GSH depletion. Collectively, these data show mechanisms whereby WA reduces necrotic hepatocyte injury, and demonstrate that WA has therapeutic potential in AILI.

Original languageEnglish (US)
Pages (from-to)122-132
Number of pages11
JournalBiochemical Pharmacology
Volume97
Issue number1
DOIs
StatePublished - Aug 22 2015

Keywords

  • Acetaminophen
  • Gclc
  • Necrosis
  • Oxidative stress
  • Withaferin-A

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Fingerprint Dive into the research topics of 'Withaferin-A Reduces Acetaminophen-Induced Liver Injury in Mice'. Together they form a unique fingerprint.

  • Cite this