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Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy

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Abstract

Paracetamol is a commonly used over-the-counter analgesic and antipyretic drug. Nevertheless, an overdose of paracetamol leads to hepatic necrosis that can be lethal. This study aimed to assess the potential hepatoprotective effects of dibenzazepine, a Notch inhibitor, against acute liver injury in rats via interfering with oxidative stress, inflammation, apoptosis, autophagy, and Notch signaling. Silymarin (200 mg/kg, p.o.) or dibenzazepine (2 mg/kg, i.p.) were administered to rats for 5 days before a single hepatotoxic dose of paracetamol (800 mg/kg, i.p.). Pretreatment with silymarin and dibenzazepine significantly mitigated oxidative stress, inflammatory and apoptotic markers induced by paracetamol hepatotoxicity where dibenzazepine showed greater repression of inflammation. Furthermore, dibenzazepine was found to be significantly more efficacious than silymarin in inhibiting Notch signaling as represented by expression of Notch-1 and Hes-1. A significantly greater response was also demonstrated with dibenzazepine pretreatment with regard to the expression of autophagic proteins, Beclin-1 and LC-3. The aforementioned biochemical results were confirmed by histopathological examination. Autophagy and Notch signaling seem to play a significant role in protection provided by dibenzazepine for paracetamol-induced hepatotoxicity in rats, which could explain its superior results relative to silymarin.

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Acknowledgments

The authors would like to thank Prof. Dr. A. Bakear (Pathology Department, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt) for his assistance in the histopathological examinations.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Lamiaa A. Ahmed & Mohamad F. El-Yamany

  2. Department of Pharmacology, Egyptian Drug Authority formerly National Organization for Drug Control and Research, Giza, Egypt

    Rana H. Abd El-Rhman, Amany M. Gad & Sherifa K. Hassaneen

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  1. Lamiaa A. Ahmed
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  2. Rana H. Abd El-Rhman
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Contributions

LAA, RHA, SKH, and MFE conceived and designed research. RHA, AMG, and SKH conducted experiments. LAA, RHA, AMG, and MFE analyzed data. RHA and LAA wrote the manuscript. All authors read and approved the final manuscript. All data were generated at National Organization for Drug Control and Research (NODCAR, Giza, Egypt), and no paper mill was used.

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Correspondence to Lamiaa A. Ahmed.

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All procedures performed in this study were conducted in accordance with the regulations approved by the Ethics Committee at Faculty of Pharmacy, Cairo University (permit number: 2385). The investigation complied with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 2011).

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Supplementary figure 1

Representative images for scores of hepatic damage; (A) No damage, score 0 revealing normal histological structure of the portal vein (pv), bile duct (bd) and the surrounding hepatocytes (h). (B) mild damage with score 1, showing few inflammatory cells infiltration in the portal area (arrow). (C) moderate damage with score 2, showing dilation and congestion in the portal vein (pv) with moderate inflammatory cells infiltration in the portal area (arrow). (D) severe damage with score 3, demonstrating hyperplasia in the bile duct (hbd), diffuse Kupffer cells (k), focal lymphoid cells aggregation (lym) and marked inflammatory cells infiltration in the portal area (arrow) (JPG 3025 kb)

Supplementary figure 2

Full-scanned images of western blots presented in Fig. 4 (JPG 753 kb)

Supplementary figure 3

Full-scanned images of western blots presented in Fig. 5 (JPG 777 kb)

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Ahmed, L.A., Abd El-Rhman, R.H., Gad, A.M. et al. Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy. Naunyn-Schmiedeberg's Arch Pharmacol 394, 337–348 (2021). https://doi.org/10.1007/s00210-020-01977-0

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