Thesis (Ph.D.) - Cairo University - Faculty of Veterinary Medicine - Department of Veterinary Pharmacology

Hepatic encephalopathy (HE) describes the array of neurological alterations that occur during acute or chronic liver injury. Hyperammonemia, oxidative stress and inflammatory injury are the main crucial factors for the pathophysiological changes associated with HE in rats. The present study was designed to evaluate the possible synergistic effect between aminoguanidine (AG; 100 mg/kg; p.o.) and l-carnosine (CAR; 100 mg/kg; p.o.) on HE that was induced by thioacetamide (TAA; 100 mg/kg.i.p) thrice weekly for six consecutive weeks. Twenty-four hours after the last treatment{u037E} behavioral changes, biochemical parameters , histopathological analysis, immunohistochemical and ultrastructural studies were conducted. The obtained results showed that combining AG with CAR improved TAA-induced locomotor impairment and motor incoordination evidenced by; reduced locomotor activity and decline in motor skill performance as well as ameliorated cognitive deficits. Moreover, both drugs restored the levels of serum hepatic enzymes as well as serum and brain levels of ammonia. In addition to, the combination significantly modulated hepatic and brain oxidative stress biomarkers, inflammatory cytokines and cleaved caspase-3 expression. Furthermore, they succeeded to activate nuclear erythroid 2-related factor 2 (Nrf2) expressions, heme oxygenase-1 (HO-1) activity and ameliorate markers of HE including hepatic necrosis and brain astrocyte swelling. This study depicts that combining AG with CAR exerted new intervention for hepatic and brain damage in HE due to their complementary antioxidant, anti-inflammatory effect and hypoammonemic effects via Nrf2/HO-1activator and NO inhibitors

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