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Activation of pCREB/Nrf-2 signaling mediates re-positioning of liraglutide as hepato-protective for methotrexate -induced liver injury (MILI)

Author:
Abdelaziz, Aya I., Mantawy, Eman M., Gad, Amany M., Fawzy, Hala M., Azab, Samar S.
Source:
Food and chemical toxicology 2019 v.132 pp. 110719
ISSN:
0278-6915
Subject:
agonists, antioxidant activity, antioxidants, apoptosis, autoimmune diseases, caspase-3, cyclic AMP, glucagon-like peptide 1, hepatocytes, hepatotoxicity, inflammation, interleukin-6, liver, methotrexate, neoplasms, oxidative stress, protective effect, rats, toxicology, transcription (genetics), transcription factor NF-kappa B, tumor necrosis factor-alpha
Abstract:
Methotrexate (MTX) is commonly used to treat several types of cancer and autoimmune diseases. However, there is increasing concern over its organs toxicities particularly liver toxicity. Liraglutide, a glucagon like peptide-1 agonist, possesses antioxidant and anti-inflammatory features. This study aimed to explore the potential protective effect of liraglutide pre-treatment in ameliorating MTX-induced hepatotoxicity and to further investigate the underlying mechanisms. Rats received 1.2 mg/kg liraglutide intraperitoneal twice daily for 7 days before MTX. Results revealed that liraglutide significantly decreased activities of liver enzymes and oxidative stress in hepatocytes. Furthermore, NF-kB expression and related inflammatory markers (TNF-α, COX-2 and IL-6) were reduced in the pre-treatment group of liraglutide. These data validate the advantageous effects of liraglutide in MTX hepatotoxic animals. In addition, liraglutide increased the expression of the antioxidant transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf-2), along with the transcription of downstream phosphorylated cAMP response element-binding protein (pCREB) which increases the activity of Nrf-2. Additionally, caspase-3 expression/activity and BAX/Bcl-2 ratio were decreased following liraglutide pre-treatment. In conclusion, it was confirmed that liraglutide enhanced the antioxidant activity of liver cells by activating the Nrf-2 and pCREB signaling, thereby, reducing liver cell inflammation and apoptosis induced by MTX.
Agid:
6553152