Hyperammonemia Induces Neuroinflammation That Contributes to Cognitive Impairment in Rats With Hepatic Encephalopathy

BACKGROUND & AIMS: Hyperammonemia and inflammation cooperate to induce neurological alterations in hepatic encephalopathy. Recent studies in animal models suggest that chronic hyperammonemia and neuroinflammation impair learning ability by the same mechanism. Chronic hyperammonemia might induce inflammatory factors in the brain that impair cognitive function. We sought to determine whether hyperammonemia itself induces neuroinflammation, whether ammonia-induced neuroinflammation mediates cognitive impairment, and whether neuroinflammation also occurs in rats with bile duct ligation (BDL rats)-a model of chronic liver injury that results in hyperammonemia and hepatic encephalopathy. METHODS: Chronic moderate hyperammonemia was induced by feeding male Wistar rats an ammonium-containing diet or performing BDL. Rats that received a standard diet or a sham operation were used as controls. Neuroinflammation was assessed by measuring activation of microglia and inflammatory factors. Brain samples were collected from hyperammonemic and BDL rats; microglial activation was determined by immunohistochemistry and quantification of inflammatory markers (ie, inducible nitric oxide synthase, interleukin-1 beta, and prostaglandin E2). Learning ability and motor activity were assessed in hyperammonemic and BDL rats given ibuprofen as an anti-inflammatory agent. RESULTS: Chronic moderate hyperammonemia or BDL activated the microglia, especially in cerebellum; increased inducible nitric oxide synthase, interleukin-1 beta, and prostaglandin E2 levels; and impaired cognitive and motor function, compared with controls. Ibuprofen reduced microglial activation and restored cognitive and motor functions in the hyperammonemic and BDL rats. CONCLUSIONS: Chronic hyperammonemia is sufficient to induce microglial activation and neuroinflammation; these contribute to the cognitive and motor alterations that occur during hepatic encephalopathy.