Mitigating Remote Organ-Induced Brain Injury in Renal Ischemia-Reperfusion: The Role of Oleuropein in Inhibiting Oxidative Stress, Inflammation, Ferroptosis, and Apoptosis in Male Rats.

Abstract

Renal ischemia-reperfusion (RIR) induces brain damage as a distant organ. Oleuropein has antioxidant properties. This study aimed to explore oleuropein's protective effects against brain injury following RIR in rats. Thirty-six male Wistar rats were divided into six groups (n = 6) including sham, oleuropein (200 mg/kg), RIR, and RIR groups treated with oleuropein (50, 100, and 200 mg/kg). 48 h after injury, blood urea nitrogen (BUN) and creatinine levels were surveyed. The western blotting analysis was performed to assay the interleukin-1 beta (IL-1β), IL-10, tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-κB p65), Bcl-2 associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), cleaved caspase-3, glutathione peroxidase-4 (GPX4), nuclear factor erythroid-related factor-2 (NRF2), solute carrier family 7, member 11 (SLC7A11), and anti-acyl-CoA synthetase long-chain family 4 (ACSL4) proteins in kidney and/or brain tissues. Also, malondialdehyde (MDA) and total antioxidant capacity (TAC) levels, the activity of GPx, catalase, and superoxide dismutase (SOD) were evaluated. Kidney and brain tissues damage scores (KTDS and BTDS) were determined by H&E staining method. Prussian blue staining was conducted to identify iron accumulation. RIR significantly increased BUN, serum creatinine levels, KTDS, BTDS, iron deposition, MDA concentration, Bax, cleaved caspase-3, IL-1β, TNF-α, NF-κB p65, ACSL4 proteins expression levels, while decreasing TAC content, SOD, GPx, and catalase activity, Bcl-2, GPX4, SLC7A11 and NRF2 proteins expression in kidney and/or brain tissue of RIR group versus the sham (P < 0.05). Moreover, oleuropein attenuated these indicators in the RIR + oleuropein (200 mg/kg) group versus the RIR group (P < 0.05). Our study showed that RIR induced brain damage, and oleuropein exhibited protective effects against brain injury induced by RIR, through inhibiting oxidative stress, inflammation, ferroptosis, and apoptosis mechanisms.