Journal Article
Novel mechanistic insights of the potential role of gasotransmitters and autophagy in the protective effect of metformin against hepatic ischemia/reperfusion injury in rats
Ahmed O. Abdel-Zaher; Marwa H. Bakr; Yomna H. Gad; Alaa T. Abdelhafez
Naunyn-Schmiedeberg's Archives of Pharmacology · Vol. 398, Issue 7 · pp. 9177-9198 · 2025
Abstract
Metformin exerts antidiabetic and pleiotropic effects. This study investigated the function and mechanisms of gasotransmitters and autophagy in the metformin-induced protection against ischemia/reperfusion injury (I/RI). According to measurements of serum hepatic function indicators and histopathological evaluation, metformin protected against hepatic I/RI-induced impairment of liver function and structure. In addition, metformin inhibited hepatic I/RI-induced hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis. Also, it suppressed hepatic I/RI-induced decrease in hepatic heme oxygenase-1 (HO-1) and hydrogen sulfide (H 2 S) levels and increase in nitric oxide (NO) production. Furthermore, metformin inhibited hepatic I/RI-induced decrease in protein expressions of endothelial NO synthase (eNOS), HO-1, cystathionine γ-lyase (CSE), and Beclin-1 and increase in the protein expression of inducible NO synthase (iNOS) in the liver tissue. Co-administration of the NO biosynthesis inhibitor, L-NAME, carbon monoxide(CO)-releasing molecule-A 1 (CORM-A 1 ), the H 2 S donor, NaHS, or the autophagy stimulator, rapamycin (RAPA), enhanced all effects of metformin. The NO donor, L-arginine, the CO biosynthesis inhibitor, zinc protoporphyrin, the H 2 S biosynthesis inhibitor, DL-propargylglycine, or the autophagy inhibitor, chloroquine (CQ), antagonized the effects of metformin. These findings reveal, for the first time, that increasing CO, H 2 S, and autophagy levels with subsequent decreasing NO level play a critical role in metformin's protective action against hepatic I/RI. The ability of L-NAME, CORM-A 1 , NaHS, and RAPA to boost metformin’s protective effect in hepatic I/RI may positively be attributed to their ability to lower hepatic oxidative stress, nitrosative stress, inflammation, and apoptosis.