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

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.

Keywords: HO-1; Heme oxygenase-1; Liraglutide; Methotrexate; Nrf 2; Nuclear factor erythroid 2-related factor2; P-CREB; Phosphorylated cAMP response element-binding protein.