Electroacupuncture with Omeprazole Synergistically Protects Against Indomethacin-Induced Colonic Injury by Activating Nrf2/HO-1 Pathway

Non-steroidal anti-inflammatory drugs (NSAIDs) like indomethacin are widely used but frequently cause severe gastrointestinal (GI) injury, including mucosal damage, ulcers, and bleeding, primarily through oxidative stress and inflammation. Current standard treatments, such as proton pump inhibitors like omeprazole, offer some protection but may not fully address the underlying oxidative damage. The Nrf2/HO-1 signaling pathway is a crucial endogenous defense mechanism against oxidative stress, regulating antioxidant and anti-inflammatory gene expression. Exploring interventions that enhance this pathway could provide a more comprehensive therapeutic strategy for NSAID-induced gastropathy.

Researchers established a gastrointestinal injury model in 30 C57BL/6J mice by intragastric administration of indomethacin (30 mg/kg). Mice were divided into normal control, model, omeprazole, combination (EA + omeprazole), and inhibitor (combination + Nrf2 inhibitor) groups, with 6 mice per group. Electroacupuncture (EA) was applied to bilateral ST36 for 20 min, a total of 2 times. Omeprazole (10 mg/kg) was given by gavage. The Nrf2 inhibitor ML385 (30 mg/kg) was administered intraperitoneally. HE staining assessed mucosal morphology. Colorimetric assays measured gastric glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD), plus colon SOD and glutathione peroxidase (GSH-Px). Flow cytometry detected colon reactive oxygen species (ROS). qPCR and Western blot quantified Keap1, Nrf2, HO-1, and NOX1 mRNA and protein expressions in colon tissue.

After indomethacin administration, the model group mice exhibited severe gastrointestinal mucosal damage compared to controls. This was characterized by significantly decreased gastric GSH content and SOD activity (P<0.01), increased MDA content (P<0.01), and elevated colon ROS levels. Furthermore, colon tissue showed increased Keap1 and NOX1 mRNA and protein expressions (P<0.01), alongside reduced SOD and GSH-Px activities (P<0.01, P<0.05), and decreased Nrf2 and HO-1 mRNA and protein levels (P<0.01).