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

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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.

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Abbreviations

VPA:

Valproic acid

TNF-α:

Tumor necrosis factor-alpha

MLKL:

Mixed lineage kinase domain-like pseudokinase

ROS:

Reactive oxygen species

RIPK1:

Receptor-interacting protein kinase 1

TNFR1:

TNF receptor 1

Tau:

Taurine

Nec-1:

Necrostatin-1

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

AST:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

MDA:

Malondialdehyde

GSH:

Glutathione

DCFH-DA:

Dichlorodihydrofluorescein diacetate

DCF:

Dichlorofluorescein

H&E:

Hematoxylin and eosin

FADD:

Fas-associated death domain

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Acknowledgements

None.

Funding

This work is related to the thesis of HA and was granted (MPRC-9721) by the Medicinal Plant Research Center of Ahvaz Jundishapur University of Medical Sciences.

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Authors and Affiliations

  1. Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Mohammad Javad Khodayar

  2. Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Mohammad Javad Khodayar, Heibatullah Kalantari & Hadis Alidadi

  3. Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Heibatullah Kalantari & Hadis Alidadi

  4. Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Layasadat Khorsandi

  5. Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Layasadat Khorsandi

  6. Department of Pharmacology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran

    Nematollah Ahangar

  7. Legal Medicine Research Center, Legal Medicine Organization, Legal Medicine Office of Khuzestan, Ahvaz, Iran

    Azin Samimi

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  1. Mohammad Javad Khodayar
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Khodayar, M.J., Kalantari, H., Khorsandi, L. et al. Taurine attenuates valproic acid-induced hepatotoxicity via modulation of RIPK1/RIPK3/MLKL-mediated necroptosis signaling in mice. Mol Biol Rep 48, 4153–4162 (2021). https://doi.org/10.1007/s11033-021-06428-4

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