Drug Res (Stuttg) 2022; 72(05): 245-254
DOI: 10.1055/a-1792-2678
Original Article

Therapeutic Potential of Isorhamnetin following Acetaminophen-Induced Hepatotoxicity through Targeting NLRP3/NF-κB/Nrf2

Ali-Mohammad Rousta
1   School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Seyed-Mohamad-Sadegh Mirahmadi
1   School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Alireza Shahmohammadi
1   School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Zhila Mehrabi
2   Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Soudabeh Fallah
3   Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Tourandokht Baluchnejadmojarad
2   Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Mehrdad Roghani
4   Neurophysiology Research Center, Shahed University, Tehran, Iran
› Author Affiliations
Funding This research project was financially supported in 2020 by National Institute for Medical Research Development (NIMAD) of Iran (grant number 987766).

Abstract

Acetaminophen (APAP)-induced acute liver injury (ALI) is the principal cause of acute liver failure (ALF) in some countries including the United States and with few available treatments. Isorhamnetin is a bioflavonoid that is found in medicinal plants like Hippophae rhamnoides L. and Ginkgo biloba L. with promising potential to regulate inflammatory responses. In this study, we evaluated the possible effect of isorhamnetin in prevention of APAP-induced ALI and analyzed further the involvement of oxidative stress and inflammation-associated factors. Male C57BL/6 mice were given isorhamnetin (25 or 100 mg/kg b.w., p.o.) three times at 48, 24, and 1 h before APAP administration (300 mg/kg b.w., i.p.). Functional indicators of liver injury were measured as well as analysis of oxidative stress- and inflammation-associated indices and liver histopathology was also conducted. Isorhamnetin at the higher dose of 100 mg/kg significantly lowered serum levels of ALT, ALP, and AST in addition to reduction of ROS, TBARS, IL-6, TNFα, NF-kB, NLRP3, caspase 1, and MPO and significantly prevented reduction of GSH, SOD activity, sirtuin 1, and Nrf2. Additionally, isorhamnetin alleviated pathological changes of the liver tissue and suitably reversed NF-kB and Nrf2 immunoreactivity. These findings show protective effect of isorhamnetin against acetaminophen-induced liver injury through reducing oxidative stress, inflammation, and pyroptosis which is attributed to its regulation of NF-kB, Nrf2, NLRP3, and sirtuin 1.



Publication History

Received: 23 December 2021

Accepted: 07 March 2022

Article published online:
31 March 2022

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