A study on the possible modulation of Notch signaling by dibenzazepine in a model of hepatotoxicity in rats / Rana Hassan Abdelrhman ; Supervised Mohammed Farrag Elyamany , Lamiaa Ahmed Ahmed , Sherifa Kamal Ahmed

Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Paracetamol is a frequently 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 (DBZ), 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 DBZ (2 mg/kg, i.p.) were administered to rats for 5 days before a single hepatotoxic dose of paracetamol (800 mg/kg, i.p.). DBZ also was given once daily 1 h after paracetamol injection and for 2 days as post-treatment. Treatment with silymarin as well as pre- and post-treatments with DBZ significantly mitigated oxidative stress, inflammatory and apoptotic markers induced by paracetamol hepatotoxicity where DBZ showed greater repression of inflammation. Furthermore, DBZ was found to be significantly more effective than silymarin in preventing Notch signaling as represented by expression of Notch-1 and Hairy and Enhancer of Split (Hes-1). A significantly better response was also demonstrated with DBZ with regard to the expression of autophagic proteins, Beclin-1 and Microtubule-associated protein 1A/1B-light chain 3 (LC-3). The aforementioned biochemical results were affirmed by histopathological examination. Autophagy and Notch signaling seem to play an important role in protection provided by DBZ for paracetamol-induced hepatotoxicity in rats, which could clarify its superior results comparative to silymarin

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