Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy.
Lamiaa A AhmedRana H Abd El-RhmanAmany M GadSherifa K HassaneenMohamad F El-YamanyPublished in: Naunyn-Schmiedeberg's archives of pharmacology (2020)
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. Graphical abstract.
Keyphrases
- oxidative stress
- diabetic rats
- cell death
- drug induced
- ischemia reperfusion injury
- dna damage
- induced apoptosis
- poor prognosis
- endoplasmic reticulum stress
- liver failure
- signaling pathway
- anti inflammatory drugs
- cell proliferation
- respiratory failure
- anti inflammatory
- mass spectrometry
- binding protein
- neuropathic pain
- heat shock
- spinal cord injury
- high glucose
- high resolution
- aortic dissection
- endothelial cells
- stress induced
- electronic health record
- high resolution mass spectrometry