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Sinapic acid mitigates methotrexate-induced hepatic injuries in rats through modulation of Nrf-2/HO-1 signaling
Ajaz Ahmad1, Khalid M Alkharfy1, Yousef A Bin Jardan2
1Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Abstract:
The present research has been investigated to study the protective outcomes of sinapic acid (SA) against methotrexate (MTX) encouraged liver damage in rats by modulating the Nrf2/HO-1 and NF-κB signaling pathways. The animals were arbitrarily allocated into four groups: group I rats administered a 0.5% carboxymethyl cellulose (CMC) vehicle orally for 15 consecutive days with a single intravenous standard saline injection (0.9% NaCl) on day seven. Groups II, III, and IV were injected intraperitoneally with 20 mg MTX/kg on 7th day. Animals in group III and IV were treated orally for 14 days with 20 mg of SA/kg dissolved daily in 0.5% CMC respectively. In all experimental groups, liver function, biochemical, histopathological and molecular changes were evaluated. MTX-induced changes in liver function indices like ALT, AST, and ALP are substantially restored with SA pretreatment. Moreover, antioxidant defense mechanisms (GSH, SOD, and CAT) and oxidative/nitrostative stress (MDA and NO) and inflammatory cytokine (TNF-α, IL-β and MPO) were also substantially restored. Furthermore, the conclusions indicate that SA prevents the hepatic damage caused by MTX through apoptosis inhibition and stimulation of Nrf2/HO-1-medial antioxidant enzymes by NF-κB inhibition. Histological findings have shown that SA therapy has greatly protected liver damage caused by MTX.
Insights
Sinapic acid (SA) protects against methotrexate (MTX)-induced liver damage in rats. SA modulates Nrf2/HO-1 and NF-κB pathways, restoring liver function and reducing oxidative stress.
Area of Science:
- Hepatology
- Pharmacology
- Toxicology
Background:
- Methotrexate (MTX) is a chemotherapy agent with known hepatotoxicity.
- Oxidative stress and inflammation are key mechanisms in MTX-induced liver injury.
- Nrf2/HO-1 and NF-κB signaling pathways play critical roles in regulating cellular responses to injury.
Purpose of the Study:
- To investigate the protective effects of sinapic acid (SA) against MTX-induced liver damage in a rat model.
- To elucidate the underlying molecular mechanisms, focusing on the modulation of Nrf2/HO-1 and NF-κB signaling pathways.
Main Methods:
- Rats were divided into four groups: control, MTX-induced liver damage, and MTX with SA treatment.
- Liver function tests (ALT, AST, ALP), oxidative stress markers (GSH, SOD, CAT, MDA, NO), and inflammatory cytokines (TNF-α, IL-1β, MPO) were assessed.
- Histopathological examination and molecular analysis of signaling pathways were performed.
Main Results:
- SA pretreatment significantly restored MTX-induced alterations in liver function enzymes.
- SA treatment normalized antioxidant defense mechanisms and reduced oxidative/nitrostative stress markers.
- SA administration suppressed inflammatory cytokine levels and inhibited apoptosis.
- Histological analysis confirmed SA's protective effect against MTX-induced hepatic damage.
Conclusions:
- Sinapic acid exhibits significant hepatoprotective effects against MTX-induced liver injury in rats.
- SA exerts its protective effects by inhibiting apoptosis and modulating the Nrf2/HO-1 and NF-κB signaling pathways.
- SA represents a potential therapeutic agent for mitigating MTX-related hepatotoxicity.
