Proteasome-driven modulation of immune and oxidative pathways during scorpion envenomation pathogenesis

Scorpion venom contains a variety of toxin molecules that are the drivers of inflammation and oxidative stress, leading to significant tissue damage. While several mechanisms underlying these responses have been studied, the involvement of the proteasome complex - a key regulator of inflammation - remains poorly understood. This study explored the role of the proteasome in modulating inflammatory and oxidative responses to envenomation by Androctonus australis hector venom.

Mice were pretreated intraperitoneally with bortezomib, a proteasome inhibitor, at low (0.05 mg/kg), medium (0.25 mg/kg), or high (0.5 mg/kg) doses, 30 minutes prior to sublethal venom administration (0.5 mg/kg, subcutaneous). Twenty-four hours after venom administration, animals were euthanized, blood and organs were collected to evaluate vascular permeability (via Evans blue dye extravasation), the extent of inflammatory cell infiltration (myeloperoxidase and eosinophil peroxidase enzymatic activities), and oxidative/nitrosative stress markers (nitric oxide, hydrogen peroxide_, malondialdehyde, catalase activity, and glutathione). Histopathological examinations were performed to identify structural alterations, such as edema, hemorrhage, and cellular infiltration. Biochemical parameters reflecting organ function, including serum levels of CPK, LDH, ALT, ALP, urea, and creatinine, were also measured to assess the degree of systemic damage.

Our findings revealed a dose-dependent immune-modulatory role of the proteasome system. A medium dose of bortezomib reduced inflammatory and oxidative stress markers, such as vascular permeability, eosinophil peroxidase, neutrophil peroxidase, nitric oxide, and malondialdehyde in renal tissue, suggesting a reduction in local inflammation and oxidative damage. In contrast, a higher dose showed pronounced preventive effects in cardiopulmonary and hepatic tissues, significantly reducing inflammatory mediators and oxidative markers, restoring antioxidant enzyme activity (catalase) and glutathione, as well as, improving tissue structure and organ function.

These findings underscore the proteasome involvement in inflammatory regulation, likely through modulation of vascular permeability, immune cell activation, and oxidative stress, making it a key target in scorpion envenomation.