Nimbolide Targeting SIRT1 Protects Against Acetaminophen-Induced Acute Liver Injury by Regulating Oxidative Stress...

Area of Science:

• Pharmacology
• Hepatology
• Toxicology

Background:

• Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI).
• N-acetylcysteine is the sole approved antidote for APAP-induced ALI.
• Nimbolide (Nim), a natural compound from the neem tree, shows promise in various disease models.

Purpose of the Study:

• To investigate the protective effects of nimbolide against APAP-induced acute liver injury in mice.
• To elucidate the underlying mechanisms, including oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial function.

Main Methods:

• An acetaminophen-induced acute liver injury model was established in male C57BL/6J mice.
• Mice were treated with nimbolide (20 mg/kg) or vehicle 2 hours prior to APAP administration (500 mg/kg).
• Liver injury, inflammation, apoptosis, oxidative stress, ER stress, mitochondrial function, and SIRT1 expression were assessed. SIRT1 knockdown was performed in vitro.

Main Results:

• Nimbolide treatment significantly alleviated APAP-induced liver injury and inflammation.
• Nimbolide inhibited APAP-induced apoptosis by regulating ER stress.
• Nimbolide improved mitochondrial function and increased Sirtuin 1 (SIRT1) expression; SIRT1 knockdown partially blocked these protective effects.

Conclusions:

• Nimbolide demonstrates significant hepatoprotective effects against acetaminophen-induced acute liver injury.
• The mechanism involves the inhibition of oxidative stress and ER stress.
• Activation of SIRT1 plays a crucial role in mediating the protective benefits of nimbolide.