Protective effect of Dapagliflozin on hepatic encephalopathy induced by thioacetamide in rats: involvement of ERK, JNK, and Nrf2/HO-1 pathways.

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with oxidative stress, neuroinflammation, and hyperammonaemia secondary to hepatic dysfunction. This study aimed to investigate dapagliflozin's effects (DAPA) against HE induced by thioacetamide (TAA) in rats and to elucidate the roles of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 (Nrf2/HO-1) signaling pathways. HE was induced by injection of TAA (200 mg/kg) intraperitoneally 2 times every other day. Two groups were pretreated with DAPA at 5 and 10 mg/kg for 15 days; on the 13th day, rats were given TAA (200 mg/kg, i.p.) twice, 2 days apart. Behavioral assessments, including object recognition and rotarod tests, were conducted, and serum and tissue samples were collected for biochemical and molecular analyses. DAPA pretreatment ameliorated TAA effects, improved recognition memory, enhanced muscular tone and motor coordination. DAPA also reduced ALT (alanine aminotransferase), AST (aspartate aminotransferase), and ammonia serum levels. Additionally, it restored antioxidant balance, decreased malonaldehyde (MDA) and increased reduced glutathione (GSH). Moreover, it reduced tissue inflammation and inhibited apoptosis; where tumor necrosis factor-alpha (TNF-α) and caspase-3 expression were suppressed. DAPA was associated with increased Nrf2/HO-1 pathway-related protein expression while decreasing pERK/total ERK and pJNK/total JNK ratios, along with nuclear factor kappa-light-chain-enhancer of activated B cells, p65 subunit (NF-κB-p65) protein expression. Histopathologically, DAPA improved hepatic and brain architecture. Collectively, DAPA exhibits hepatoprotective and neuroprotective effects against TAA-induced HE accompanied by modulation in oxidative-, inflammatory-, and apoptotic-related protein expression, highlighting its therapeutic potential in hepatic encephalopathy.