Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways

• Published in: Bioorganic chemistry 2020-12, Vol.105, p.104444, Article 104444
• Main Authors: Baraka, Sara M., Saleh, Dalia O., Ghaly, Neveen S., Melek, Farouk R., Gamal el Din, Amina A., Khalil, Wagdy K.B., Said, Mahmoud M., Medhat, Amina M.
• Format: Article
• Language: English
• Subjects: Animals; Barnebydendron riedelii; Behavior Rating Scale; Body Weight - drug effects; Chemical and Drug Induced Liver Injury - prevention & control; Dose-Response Relationship, Drug; Drug Discovery; Flavonoids - isolation & purification; Flavonoids - pharmacology; Glial Fibrillary Acidic Protein - metabolism; Heme Oxygenase-1 - metabolism; Hepatic Encephalopathy - ethnology; Hepatic Encephalopathy - prevention & control; Hepatoprotective; Humans; Hyperammonemia; Interleukin-6 - metabolism; Liver - metabolism; Magnoliopsida - chemistry; Male; Molecular Docking Simulation; Neuromodulatory; Neurotransmitter Agents - isolation & purification; Neurotransmitter Agents - pharmacology; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Oxidative Stress - drug effects; Plant Extracts - chemistry; Plant Extracts - pharmacology; Plant Leaves - chemistry; Rats; Rats, Wistar; Signal Transduction; Thioacetamide - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104444

[Display omitted] •Flavonoids from Barnebydendron riedelii leaf extract showed beneficial effects against hepatic encephalopathy.•Flavonoid containg butanol fraction improved motor impairment, cognitive deficits and serum hepatotoxic biomarkers.•Modulatory effects of flavonoidal content on NF-κB/IL-6 and Nrf2/HO-1 signaling pathways.•Flavonoidal content ameliorated liver and brain histopathological changes as well as apoptotic marker; Caspase-3. Phytochemical investigation of the butanol fraction (BUF) derived from the 70% aqueous methanolic leaf extract of Barnebydendron riedelii led to the isolation of three flavonoid glycosides; kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside, quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-galactopyranoside and quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside. Docking studies were fulfilled to validate the possible bio-properties of BUF toward nuclear factorkappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). The protective role of BUF against behavioral, biochemical, molecular, histopathological and immunohistochemical alterations in thioacetamide (TAA)-induced hepatic encephalopathy in rats was investigated. The toxicological studies indicated that BUF was safe up to 2000 mg/kg bw. Prior to TAA intoxication, rats were orally treated with either BUF at multiple doses (70, 140 and 280 mg/kg bw) or lactulose (8 mL/kg bw) for 14 consecutive days. On the 13th and the 14th day, TAA (200 mg/kg bw/day) was intraperitoneally injected. The BUF significantly improved motor impairment, ameliorated cognitive deficits and attenuated TAA-induced hepatotoxicity. Moreover, BUF controlled the inflammatory processes by suppressing the hepatic inflammatory cytokine; interleukin-6 (IL-6) as well as its pro-inflammatory mediator; NF-κB supporting the molecular docking assessment. The brain neurotransmitters; dopamine, serotonin and noradrenaline, as well as ammonia levels were improved in BUF-treated TAA-intoxicated animals in a dose-dependent manner. Furthermore, BUF administration to TAA-intoxicated rats modulated the Nrf2 and heme oxygenase 1 (HO-1) genes expression in liver and brain tissues. The histological evaluation showed that pretreatment of TAA-intoxicated rats with BUF ameliorated the degenerative effects of TAA on liver and brain tissues as well as reduced the activation of cellular apoptotic marker; caspase-3 and glial fibrillary acidic protein (GFAP+) astrocytes. In conclusion, t