Therapeutic potentials of trihydroxylflavonone-7-rhamnoglucoside against hepatocellular Lesch-Nyhan Syndrome induced by mixture of caffeine and KBrO3 via NOS/cAMP/PKA and DARPP-32, BDNF/TrkB signaling cascades

Abstract

The management of Lesch-Nyhan Syndrome (LNS) associated with hepatocellular toxicosis has remained in the speculative phase. Also, due to numerous pharmacological capacities of 4,5,7-Trihydroxylflavonone-7-rhamnoglucoside popularly known as naringin, it may be a potent therapeutic flavonoid against hepatic LNS. We therefore studied the effect of 4,5,7-Trihydroxylflavonone-7-rhamnoglucoside on rats’ hepatic cells exhibiting LNS through NOS/cAMP/PKA/DARPP-32 and BDNF/TrkB signaling pathways. Sixty-seven male rats were divided into nine (n = 7) groups. Group I received distilled water only. Group II and III were exposed to 100 mg/kg KBrO₃ and 250 mg/kg caffeine, respectively. Group IV was co-exposed to 100 mg/kg KBrO₃ and 250 mg/Kg caffeine. Group V and VI were exposed to 100 mg/kg KBrO₃ each plus 100 mg/kg haloperidol and 50 mg/kg naringin, respectively. Group VII received 250 mg/kg caffeine + 50 mg/kg naringin. Group VIII received 100 mg/kg KBrO₃ + 250 mg/kg caffeine + 50 mg/kg naringin. Group IX received 50 mg/kg naringin. Exposure to KBrO₃ and/or caffeine for 21 days induced hepatocellular damage with alterations of ATP hydrolytic enzymes, neurotransmitter enzymes, arginase, PDE-5¹, MDA and NO levels. Also, genes associated with hepatic LNS were up-regulated and characterized by periportal inflammation and vascular congestion. Post-treatment with 4,5,7-Trihydroxylflavonone-7-rhamnoglucoside for 14 days reverted the hepatic LNS in an in vivo model. We therefore concluded that bio-stimulation of TrKB/BDNF and DARPP-32 levels by 4,5,7-Trihydroxylflavonone-7-rhamnoglucoside may prolong the functionality of liver among individuals suffering from LNS.