Alizarin Mitigates Paracetamol-Induced Hepatorenal Injury in Mice via Modulation of the Nrf2/HO-1/NFκB/Apoptosis Pathway

Abstract

Paracetamol (Para) is a commonly employed nonsteroidal anti-inflammatory agent recognized for its potent analgesic and antipyretic effects; nevertheless, its use is often associated with severe hepatonephrotoxic side effects. Alizarin (ALZ), an anthraquinone compound, demonstrates antiproliferative and strong radical-scavenging properties. However, it remains unknown whether ALZ has any effects on hepatonephrotoxicity caused by the use of these drugs. This study investigated how ALZ modulates Paracetamol-induced liver and kidney toxicity in mice, with particular emphasis on the induction of the Nrf2/HO-1 regulatory pathway. For this purpose, ALZ (25 and 50 mg/kg, p.o.) and Para (250 mg/kg, p.o.) were applied to male mice for a duration of 14 days to induce hepatonephrotoxicity. ALZ administration alleviated the elevated biochemical indicators (ALT, AST, BUN, ALP, and creatinine) caused by Para. Additionally, ALZ reduced lipid peroxidation by decreasing MDA levels in tissues and improved antioxidant levels by increasing GSH, SOD, and CAT levels. Moreover, ALZ enhanced the mRNA expression levels of HO-1, Nrf2, and Bcl-2, which had been reduced by inflammation, oxidative stress, and apoptotic processes, while suppressing the increased gene expression levels of Bax, NF kappa B, Cas-3, and TNF-alpha. Furthermore, ALZ regulated the protein expression levels of Bax, Nrf2, Bcl-2, and Cas-3, which were altered by Para administration. Histopathological evaluations revealed that ALZ alleviated the tissue injuries in the liver and kidneys induced by Paracetamol. Overall, ALZ demonstrated a protective effect against Para-related hepatonephrotoxicity by attenuating oxidative stress, inflammatory responses, and apoptotic activity through Upregulation of the Nrf2/HO-1 signaling cascade. These results indicate that ALZ has potential therapeutic effects against liver and kidney damage.