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Melatonergic Modulation of SIRT1-Nrf2 Signaling Protects Against Doxorubicin-Induced Hepatic Injury in Rats
Haluk Kerim Karakullukcu1, Hatice Aygun2, Murat Kalın1
1Department of General Surgery, Sultan 2. Abdulhamid Han Educational and Research Hospital, University of Health Sciences, Istanbul 34668, Türkiye.
Biomedicines
|July 28, 2026
Summary
Melatonin and agomelatine protect against doxorubicin-induced liver injury by reducing oxidative stress and inflammation. These melatonergic drugs offer a promising strategy for mitigating chemotherapy side effects.
Area of Science:
- Pharmacology
- Hepatology
- Biochemistry
Background:
- Doxorubicin (DOX) is a potent chemotherapeutic agent with significant clinical utility.
- Hepatotoxicity, driven by oxidative stress and inflammation, limits Doxorubicin's use.
- Melatonin and agomelatine are potential therapeutic agents for mitigating drug-induced liver injury.
Purpose of the Study:
- To evaluate the protective effects of melatonin and agomelatine against Doxorubicin-induced liver injury.
- To investigate the impact of these agents on oxidative stress, inflammation, and specific molecular markers.
Main Methods:
- Rats were divided into Control, Doxorubicin (DOX), DOX + Melatonin, and DOX + Agomelatine groups.
- Melatonin and agomelatine were administered as a one-week pretreatment before DOX injection.
- Hepatic injury assessed via scintigraphy (99mTc-PYP uptake), liver enzymes (AST, ALT, LDH), oxidative stress markers (MDA, GSH, Nrf2, SIRT1), and inflammatory cytokines (TNF-α, IL-6, IL-10).
Main Results:
- DOX significantly elevated liver enzymes, 99mTc-PYP uptake, MDA, TNF-α, and IL-6, while decreasing GSH, Nrf2, SIRT1, and IL-10.
- Melatonin and agomelatine treatments significantly reduced liver damage markers and oxidative stress.
- Both agents attenuated inflammatory responses and restored levels of antioxidant markers (GSH, Nrf2, SIRT1).
Conclusions:
- Melatonin and agomelatine effectively attenuated Doxorubicin-induced hepatotoxicity.
- Protective mechanisms involve reducing oxidative stress, modulating inflammation, and restoring Nrf2 and SIRT1 pathways.
- Melatonergic interventions show promise for preventing Doxorubicin-related liver injury.
