Modulation of ER Stress via cAMP Signaling: Protective Role of Rolipram in Paracetamol-Induced Liver Injury

This investigation sought to assess the potential protective function of the phosphodiesterase-4 (PDE) enzyme inhibitor rolipram (ROL) against paracetamol (PARA) induced liver damage, as well as any potential underlying mechanism through modulation of endoplasmic reticulum (ER) stress via cAMP signaling. Fifty-six rats were randomly divided into 7 groups (n = 8). Following 24 h of fasting, animals received three different dosages of ROL (1.25, 2.5, and 5 mg/kg, i.p.) or N-acetylcysteine (140 mg/kg, orally). One hour later, 2 g/kg PARA orally was administered to induce hepatotoxicity. The ELISA method was used to evaluate GSH, PDE4D, and cAMP levels in liver tissue, as well as PDE4D and cAMP levels in serum. In addition, serum levels of liver injury biomarkers, including ALT and AST, were measured. GRP78, IRE1, and CHOP mRNA expressions in tissue samples were assessed using the Real Time PCR technique. The liver tissue's histopathological parameters, including necrosis, bleeding, and mononuclear cell infiltration, were evaluated. The PARA group had higher serum and tissue PDE4 levels, lower cAMP and GSH levels, higher ALT and AST levels, and higher expressions of the ER stress markers GRP78, IRE1, and CHOP mRNA. Histopathological evaluation also revealed severe histopathological damage with PARA toxicity. These changes improved with dose dependent increase of ROL dose. It was evaluated that the protective effect of PDE4 enzyme inhibition on liver injury caused by PARA toxicity could be regulated by intracellular secondary communication signals and ER stress inhibition. These findings also suggested that these pathways might be studied in relation to other liver injuries.