Luminespib protects against dexamethasone-induced hepatic, vascular, and metabolic abnormalities in rats

Area of Science:

• Biochemistry
• Pharmacology
• Toxicology

Background:

• Dexamethasone (DEX) is widely used but causes metabolic and vascular toxicity.
• Luminespib (LUM), an HSP90 inhibitor, shows promise in oncology.
• No studies have investigated LUM's protective effects against DEX-induced toxicity.

Purpose of the Study:

• To investigate the protective effects of LUM against DEX-induced hepatic and vascular toxicity in rats.
• To elucidate the underlying mechanisms of LUM's protective action.

Main Methods:

• Adult male Wistar rats were treated with DEX to induce toxicity.
• LUM was administered at two doses (2.5 and 5 mg/kg) before DEX.
• Evaluated hepatic steatosis, liver enzymes, aortic injury, and metabolic parameters.
• Assessed cellular oxidant balance, inflammatory markers, HSP90/GR expression, ER stress, and protein degradation pathways.

Main Results:

• LUM significantly ameliorated DEX-induced hepatic steatosis, elevated liver enzymes (ALT, AST, LDH), aortic injury, and metabolic abnormalities (fasting insulin, OGTT).
• Protective effects were linked to restored oxidant balance (GSH, MDA, NO), reduced inflammation (NF-κB/TNF-α/MCP-1), HSP90 inhibition, decreased glucocorticoid receptor (GR) expression, and reduced ER stress (CHOP, PERK).
• LUM activated proteasomal and autophagic degradation pathways for misfolded GR.

Conclusions:

• Luminespib demonstrates significant protective effects against dexamethasone-induced hepatic and vascular toxicity.
• The mechanism involves modulating oxidative stress, inflammation, ER stress, and protein degradation pathways.
• LUM holds therapeutic potential for optimizing dexamethasone treatment outcomes.