Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy
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ORIGINAL ARTICLE
Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy Lamiaa A. Ahmed 1
&
Rana H. Abd El-Rhman 2 & Amany M. Gad 2 & Sherifa K. Hassaneen 2 & Mohamad F. El-Yamany 1
Received: 15 April 2020 / Accepted: 13 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Autophagy . Dibenzazepine . Hepatotoxicity . Notch . Paracetamol
Introduction Paracetamol is a commonly used antipyretic and analgesic drug with weak antiinflammatory activity (James et al. 2003). It is considered nontoxic at therapeutic doses (10–15 mg/kg) (Rumack 2004; Larson 2007; Jaeschke 2015). However, paracetamol overdose causes lethal hepatotoxicity that leads to liver injury both in experimental animals (Galal
et al. 2012; Prabu et al. 2017; Papackova et al. 2018) and in humans (McGill et al. 2012; Jaeschke 2015). Cytochrome P450–mediated metabolism of paracetamol generates reactive oxygen species (ROS), leading to subsequent liver injury. Cell death is caused by the toxic paracetamol metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), that activates Kupffer cells to produce inflammatory cytokines such as interleukin-12 (IL-12), IL-18, and tumor necrosis
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01977-0) contains supplementary material, which is available to authorized users. * Lamiaa A. Ahmed [email protected] Rana H. Abd El-Rhman [email protected]
Mohamad F. El-Yamany [email protected]
1
Department of Pharmacology and Toxicology, Faculty
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