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AbstractAmmonia is produced continuously in the body It crosses the blood-brainbarrier readily and at increased concentration it is toxic to the brainSildenafil has been successfully used to treat patients withcardiovascular diseases It can also elevate localized cerebral bloodflow in rat brain We therefore tested the hypothesis that sildenafilcitrate has a protective effect on the brain functions in hyperammonemicrats Sildenafil citrate administration resulted in a significantreduction in liver enzymes lipid profile lipid peroxidation caspase-3mRNA and elevation in cyclic guanosine monophosphate cGMP nitricoxide NO antioxidant levels as well as endothelial nitric oxidesynthase eNOS gene expression in the brains of hyperammonemic ratsOur results show that sildenafil exerts a protective effect on brain byreversing the oxidant-antioxidant imbalance during ammoniumchloride-induced hyperammonemia and this could be due to its icytoprotective effect ii antioxidant properties iii anti-apoptoticeffect iv increasing cGMP and v enhancing the proper metabolism offats which could suppress oxygen radical generation and thus preventoxidative damage in the brain Consequently therapeutic modulation ofthe eNOScGMP interaction might have important clinical applications toimprove current antihyperammonemic agents in patients withhyperammonemia or clinical hepatic encephalopathy Hyperammonaemia is a metabolic disturbance characterized by an excess of HYPERLINK httpenwikipediaorgwikiAmmonia o Ammonia ammonia in the blood Chepkova et al 2006 It is a major contributing factorto neurological abnormalities observed in hepatic encephalopathy and incongenital defects of ammonia detoxification including impairedintellectual function Chepkova et al 2005 Elevated levels ofammonia cause irritability somnolence vomiting seizures andderangement of cerebral function coma and death Mathias et al 2001Ammonia toxicity results in free-radical generation that leads tooxidative stress and tissue damage and increased entry of ammonia to thebrain is a primary cause of neurological disorders associated withhyperammonemia such as hepatic encephalopathy Reye syndrome severalother metabolic disorders and other toxic encephalopathies Murthy etal 2001 A 5- to 10-fold increase in ammonia in the blood inducesN-methyl-D-aspartate receptor-mediated toxic effects in most animalspecies and alters the central nervous system functions Lena andSubramanian 2004 Majeed 2005 Sildenafil citrate C22H30N8O4SSildenafil is a selective inhibitor of phosphodiestrase-5
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