RESUMEN
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.
Asunto(s)
Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Autofagia/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Dibenzazepinas/uso terapéutico , Sustancias Protectoras/uso terapéutico , Receptor Notch1/metabolismo , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Dibenzazepinas/farmacología , Interleucina-6/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Malondialdehído/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley , Receptor Notch1/genética , Transducción de Señal/efectos de los fármacos , Factor de Transcripción HES-1/genética , Factor de Transcripción HES-1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The purpose of the present study was to investigate the effects of garlic (Allium sativum L.) on the diabetic nephropathy and oxidative stress induced by STZ (streptozotocin) in rats. Diabetes was induced in Male Sprague-Dawley rats by administering a single intraperitoneal injection of STZ (60 mg/kg of body weight). Administration of garlic, prepared as FGH (fresh garlic homogenate) significantly attenuated STZ-induced diabetic nephropathy as evaluated by assessment of serum glucose, insulin, total TAG (triacylglycerol), TC (total cholesterol) and Ccr (creatinine clearance) in control and STZ-induced diabetic rats. Urinary excretions of albumin and NAG (N-acetyl-beta-D-glucosaminidase) were also reduced following the treatment with FGH. In addition, significant inhibition of TBARSs (thiobarbituric acid-reacting substances) with a marked improvement of GSH content in the kidney homogenates was also observed. Moreover, renal tissue content and urinary excretion of nitrites were markedly decreased in this model, and virtually enhanced to the same levels as in the non-diabetic kidney following FGH supplementation. These data revealed that FGH has the ability to ameliorate STZ-induced diabetic nephropathy possibly through participation in the inhibition of oxidative damage to kidney and/or increased kidney nitric oxide bioavailability.