Green synthesized cerium oxide nanoparticles ameliorate hepatic and cognitive dysfunctions in thioacetamide-induced hepatic encephalopathy in rats: Modulation of TLR-4/NF-?B/Caspase-3 signaling pathways

This study reports an ecofriendly approach to cerium oxide nanoparticles (CeO2NPs) biosynthesis using the alcoholic extract of Carissa carandas aerial parts. The total phenolic content (mg GAE/g extract) and total flavonoid content (mg CE/g extract) of alcoholic extract of C. carandas aerial parts were 130.19 & PLUSMN; 0.78 and 124.02 & PLUSMN; 0.28, respectively. Moreover, the results of high performance liquid chromatography analysis revealed the identification of 18 different phenolic compounds of the plant extract. The hepato and neuroprotective efficacy of biosynthesized CeO2NPs was assessed against behavioral, biochemical, molecular, and histopathological alterations in a hyperammonemic rat model induced by thioacetamide (TAA). Docking studies were performed to explore the binding affinities of CeO2NPs toward toll like receptor-4 (TLR-4), monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and Caspase-3. Rats received an intravenous injection of bio-synthesized CeO2NPs at doses 0.1 and 0.5 mg/kg bw twice weekly for 4 weeks along with an intraperitoneal injection of TAA (200 mg/kg bw). The X-ray diffraction, N2 ads./des, scanning electron microscopy, particle size and zeta potential results confirmed the CeO2 fingerprint with a particle size 112 nm showing nice dispersion stability (-20.8 mV) and very good surface area 185.6 m2/g which reflecting a good nanomaterial character. Administration of CeO2NPs improved exploratory and cognitive deficits, as well as serum hepatic toxicity indices. CeO2NPs effectively preserved the antioxidant status, modulated the brain neurotransmitters, ammonia content and AChE activity. The neuro-inflammatory process was lessened by CeO2NPs, as indicated by a significant downregulation of brain TLR-4 and nuclear factor & kappa;B (NF-& kappa;B) genes expression. The histopathological findings outlined the protective role of CeO2NPs against the damaging impacts of TAA on liver and brain tissues. Moreover, the anti-apoptotic effect of CeO2NPs was detected by a significant decline in Caspase-3 immunoexpression in liver and brain tissues. Moreover, the docking studies of CeO2NPs exhibited high binding affinity interactions toward AChE (-14.43 kcal/mol), MAO-A (-24.51 kcal/mol), MAO-B (-2.50 kcal/mol), TLR-4 (-17.28 kcal/mol) and Caspase-3 (-5.03 kcal/mol). In conclusion, the biosynthesized CeO2NPs exhibit hepato and neuroprotective effects in hepatic encephalopathy rat model by exerting anti-oxidative, anti-inflammatory and anti-apoptotic properties.