Taurine attenuates valproic acid-induced hepatotoxicity via modulation of RIPK1/RIPK3/MLKL-mediated necroptosis signaling in mice.

Abstract

Valproic acid (VPA) is known as a common drug in seizure and bipolar disorders treatment. Hepatotoxicity is the most important complication of VPA. Taurine (Tau), an amino acid, has antioxidant effects. The present research was conducted to evaluate the protective mechanisms of Tau on VPA-induced liver injury, especially focusing on the necroptosis signaling pathway. The sixty-four male NMRI mice were divided into eight groups with eight animals per each. The experiment groups pretreated with Tau (250, 500, 1000 mg/kg) and necrostatine-1 (Nec-1, 1.8 mg/kg) and then VPA (500 mg/kg) was administered for 14 consecutive days. The extent of VPA-induced hepatotoxicity was confirmed by elevated ALP (alkaline phosphatase), AST (aspartate aminotransferase), ALT (alanine aminotransferase) levels, and histological changes as steatosis, accumulation of erythrocytes, and inflammation. Additionally, VPA significantly induced oxidative stress in the hepatic tissue by increasing ROS (reactive oxygen species) production and lipid peroxidation level along with decreasing GSH (glutathione). Hepatic TNF-α (tumor necrosis factor) level, mRNA and protein expression of RIPK1 (receptor-interacting protein kinase 1), RIPK3, and MLKL (mixed lineage kinase domain-like pseudokinase) were upregulated. Also, the phosphorylation of MLKL and RIPK3 increased in the VPA group. Tau could effectively reverse these events. Our data suggest which necroptosis has a key role in the toxicity of VPA through TNF-α-mediated RIPK1/RIPK3/MLKL signaling and oxidative stress. Our findings suggest that Tau protects the liver tissue against VPA toxicity via inhibiting necroptosis signaling pathway mediated by RIPK1/RIPK3/MLKL and suppressing oxidative stress, and apoptosis.

• Authors: Mohammad Javad Khodayar, Heibatullah Kalantari, Layasadat Khorsandi, Nematollah Ahangar, Azin Samimi, Hadis Alidadi
• Journal: Molecular biology reports (Mol Biol Rep) Vol. 48 Issue 5 Pg. 4153-4162 (May 2021) ISSN: 1573-4978 [Electronic] Netherlands
• PMID: 34032977 (Publication Type: Journal Article)

Chemical References

• Imidazoles
• Indoles
• Protective Agents
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• necrostatin-1
• Taurine
• Valproic Acid
• MLKL protein, mouse
• Protein Kinases
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk1 protein, mouse
• Ripk3 protein, mouse

Topics

• Animals
• Apoptosis (drug effects)
• Chemical and Drug Induced Liver Injury (drug therapy, etiology, metabolism)
• Imidazoles (administration & dosage)
• Indoles (administration & dosage)
• Male
• Mice
• Necroptosis (drug effects)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• Protective Agents (administration & dosage)
• Protein Kinases (metabolism)
• Reactive Oxygen Species (metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction (drug effects)
• Taurine (administration & dosage)
• Tumor Necrosis Factor-alpha (metabolism)
• Valproic Acid (administration & dosage, radiation effects)