Inflammation and hepatic encephalopathy: Ibuprofen restores learning ability in rats with portacaval shunts

Abstract

One of the neurological alterations in patients with minimal or overt hepatic encephalopathy is cognitive impairment. This impairment is reproduced in rats with chronic liver failure due to portacaval shunt (PCS). These rats show decreased ability to learn a conditional discrimination task in a Y-maze, likely due to reduced function of the glutamate-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in brain. It has been proposed that inflammation exacerbates the neuropsychological alterations induced by hyperammonemia, suggesting that inflammation-associated alterations may contribute to cognitive impairment in hepatic encephalopathy. This study assessed whether treatment with an anti-inflammatory drug, ibuprofen, is able to restore the function of the glutamate-NO-cGMP pathway in cerebral cortex in brain in vivo and/or learning ability in PCS rats. We show that PCS rats have increased levels of interleukin-6 and increased activities of cyclooxygenase and of inducible NO synthase in cerebral cortex, indicating the presence of inflammation. Chronic treatment with ibuprofen normalizes cyclooxygenase and inducible NO synthase activities but not interleukin-6 levels. Moreover, ibuprofen normalizes the function of the glutamate-NO-cGMP pathway in cerebral cortex in vivo and completely restores the ability of rats with chronic liver failure to learn the Y-maze task. Learning ability is also impaired 1 in rats with chronic liver failure due to portacaval shunt (PCS). In this model the function of the glutamate-NO-cGMP pathway is impaired in cerebellum 2 and cerebral cortex 3 in vivo. Moreover, increasing cGMP in brain by administration of phosphodiesterase inhibitors restores learning ability of PCS rats, 1 indicating that reduced cGMP formation is responsible for impaired learning. However, the factors and mechanisms by which chronic liver failure impairs the function of this pathway and learning ability remain unclear.Shawcross et al. 4 proposed that inflammation exacerbates the neuropsychological alterations induced by hyperammonemia. Chung et al. 5 also showed that a nonsteroidal anti-inflammatory drug (NSAID), indomethacin, prevents the development of ammonia-induced brain edema in rats after portacaval anastomosis. These reports support the idea that hyperammonemia and inflammation cooperate in the cerebral alterations present in hepatic encephalopathy. There is also increasing evidence that inflammatory mechanisms are involved in the cognitive impairment in patients with Alzheimer's disease. Epidemiologic studies show that patients (e.g., with arthritis) treated with anti-inflammatory drugs such

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

“…19 In an animal model of MHE, Cauli and colleagues demonstrated an improved learning ability following the administration of the NSAID, ibuprofen. 71 This may act by reducing the inducible nitric oxide activity within the cerebral cortex. In chronic liver disease experimental models, portal vein ligated animals have not been found to exhibit microglial activation, however, feeding rats an ammoniumcontaining diet or performing bile duct ligation (BDL) was sufficient to induce microglial activation and neuroinflammation which was reduced by administering ibuprofen.…”

“…103 In a chronic portocaval-shunted rat model, Cauli and colleagues showed that the NSAID ibuprofen restored the ability of the rats to learn the Y-task maze, in addition to normalization of the function of the glutamate-nitric oxide cyclic guanosine monophosphate enzyme pathway in the cerebral cortex. 71 Unfortunately, NSAID drugs can only have a limited role in the treatment of HE in patients with cirrhosis as they have adverse cardiovascular and renal toxicities which impact upon the protective role of prostaglandins in cellular metabolism.…”

Pregnenolone Sulfate Restores the Glutamate-Nitric-Oxide-cGMP Pathway and Extracellular GABA in Cerebellum and Learning and Motor Coordination in Hyperammonemic Rats

“…This glutamate-NO-cGMP pathway is impaired in cerebellum of rats with chronic hyperammonemia without 13 or with 14 liver failure. Restoring the pathway and cGMP formation with sildenafil, a phosphodiesterase 5 inhibitor, 14 ibuprofen, an anti-inflammatory, 15 or antagonists of GABA A receptors as bicuculline, 16 restore learning in hyperammonemic rats. However, these treatments may have secondary effects in cirrhotic patients and new psychopharmacological agents are necessary.…”

Evaluation of Relation Between Air Pollution and Hepatic Encephalopathy Exacerbation

“…Experimental studies results show that, epithelial cells produce increased amounts of IL-6, IL-8, or fibronectin following ozone exposure and both IL-6 and fibronectin are secreted vectorially [31]. Animal studies suggesting that inflammationassociated alterations may contribute to cognitive impairment in hepatic encephalopathy [32]. Higher levels of TNFα and IL-6 are detectable in the serum of patients with fulminant hepatitis and cirrhosis [33,34] and inflammatory cytokines in patients with infections and liver disease could influence brain function at different levels including the cerebral endothelial cell and Astrocytes [35].…”