CIGB-258, a Potential Novel Approach to Treat Sepsis-like Hyperinflammation, Reduces Gastrointestinal Hemorrhage in Zebrafish Exposed to Carboxymethyllysine and Ethanol

<b>Objective:</b> CIGB-258 is a 3 KDa altered peptide ligand recognized for its anti-inflammatory activity. Herein, the effect of CIGB-258 was assessed against carboxymethyllysine (CML) and ethanol (Et-OH)-induced sepsis-like events in zebrafish (<i>Danio rerio</i>). <b>Methodology:</b> Adult zebrafish (n = 30/group) were intraperitoneally microinjected (10 μL) with CML (final 3 mM) + Et-OH (final 50%) or CML + Et-OH containing CIGB-258 (final 1 μM) and analyzed for swimming activity, abdominal bleeding and survivability. The zebrafish were sacrificed 180 min after injection, and blood and organs were processed for biochemical and histological evaluation. <b>Results:</b> The CML + Et-OH group showed the lowest survival, compromised swimming ability, and severe abdominal bleeding 60 min post-treatment, which were substantially improved by treatment with CIGB-258. The CML + Et-OH group showed the greatest extent of oxidization and the lowest antioxidant activity in plasma, while co-treatment with CIGB-258 resulted in a remarkable improvement in oxidative extent and antioxidant status. The CML + Et-OH group showed dyslipidemia and an atherogenic lipid profile, which were substantially prevented by the CIGB-258 treatment. The livers and kidneys of the CML + Et-OH group showed the greatest extent of inflammation and senescence, which were substantially ameliorated by treatment with CIGB-258. Similarly, the CML + Et-OH group exhibited severe intestinal bleeding, which decreased 2.2-fold following treatment with CIGB-258. H&E staining and Mason-trichrome staining revealed extreme disruption to intestinal microvillus cell morphology and severe fibrosis in the intestines of the CML + Et-OH group, which effects were mitigated by the treatment with CIGB-258. <b>Conclusions:</b> The CML + Et-OH treatment resulted in acute gastrointestinal bleeding, severe oxidative stress, and hepatic and renal damage, leading to acute septic shock-like death in zebrafish. However, treatment with CIGB-258 reduced these effects through antioxidant and anti-inflammatory actions and by increasing HDL-C levels.