Cerebellar spongiform degeneration is accompanied by metabolic, cellular, and motor disruption in male rats with portacaval anastomosis.

The episodes of cerebral dysfunction, known as encephalopathy, are usually coincident with liver failure. The primary metabolic marker of liver diseases is the increase in blood ammonium, which promotes neuronal damage. In the present project, we used an experimental model of hepatic encephalopathy in male rats by portacaval anastomosis (PCA) surgery. Sham rats had a false operation. After 13 weeks of surgery, the most distinctive finding was vacuolar/spongiform neurodegeneration exclusively in the molecular layer of the cerebellum. This cerebellar damage was further characterized by metabolic, histopathological, and behavioral approaches. The results were as follows: (a) Cellular alterations, namely loss of Purkinje cells, morphological changes, such as swelling of astrocytes and Bergmann glia, and activation of microglia; (b) Cytotoxic edema, shown by an increase in aquaporin-4 and N-acetylaspartate and a reduction in taurine and choline-derivate osmolytes; (c) Metabolic adjustments, noted by the elevation of circulating ammonium, enhanced presence of glutamine synthetase, and increase in glutamine and creatine/phosphocreatine; (d) Inflammasome activation, detected by the elevation of the marker NLRP3 and microglial activation; (e) Locomotor deficits in PCA rats as assessed by the Rotarod and open field tests. These results lead us to suggest that metabolic disturbances associated with PCA can generate the cerebellar damage that is similar to morphophysiological modifications observed in amyloidogenic disorders. In conclusion, we have characterized a distinctive cerebellar multi-disruption accompanied by high levels of ammonium and associated with spongiform neurodegeneration in a model of hepatic hypofunctioning.

N - 3 fatty acids during chemotherapy: toward a higher level of evidence for clinical application.

PURPOSE OF REVIEW: Recommendations for intakes of n - 3 fatty acids (FAs) in patients who are receiving chemotherapy for cancer are based on weak evidence. This review highlights themes within the emergent literature to suggest improvements in the design of studies that provide n - 3 FA supplements concurrent with cytotoxic agents. RECENT FINDINGS: Following earlier research in animal models and human pilot studies, recent human studies have evaluated the effect of providing n - 3 FAs during delivery of single agent and multiagent chemotherapy regimens for breast and gastro-intestinal cancers. Regimens were based on platinum compounds, fluoropyrimidines or both, and a variety of additional agents. Tumor location and stage, supplement dose and duration, and endpoints were dissimilar across studies. Overall, the recent research continues to support the safety and tolerability of n - 3 FA supplementation with chemotherapy and provides additional evidence, albeit weak, for enhanced tumor response, maintenance of weight and muscle, and reduction in inflammation and toxicities in the host across multiple cancer sites and chemotherapy regimens. SUMMARY: The barriers to implementation in practice remain small study sizes, variations in supplement dosage and methodology, and differences in primary endpoints. Randomized, blinded trials with a justifiable sample size, adequate doses, monitored compliance and measures of clinically important endpoints are required to move these findings to a higher level of evidence for implementation into clinical practice.

Reduced Liver Lipid Peroxidation in Subcellular Fractions Is Associated with a Hypometabolic State in Rats with Portacaval Anastomosis.

A surgical connection between portal and inferior cava veins was performed to generate an experimental model of high circulating ammonium and hepatic hypofunctioning. After 13 weeks of portacaval anastomosis (PCA), hyperammonemia and shrinkage in the liver were observed. Low glycemic levels accompanied by elevated levels of serum alanine aminotransferase were recorded. However, the activity of serum aspartate aminotransferase was reduced, without change in circulating urea. Histological and ultrastructural observations revealed ongoing vascularization and alterations in the hepatocyte nucleus (reduced diameter with indentations), fewer mitochondria, and numerous ribosomes in the endoplasmic reticulum. High activity of hepatic caspase-3 suggested apoptosis. PCA promoted a marked reduction in lipid peroxidation determined by TBARs in liver homogenate but specially in the mitochondrial and microsomal fractions. The reduced lipoperoxidative activity was also detected in assays supplemented with Fe2+. Only discreet changes were observed in conjugated dienes. Fluorescent probes showed significant attenuation in mitochondrial membrane potential, reactive oxygen species (ROS), and calcium content. Rats with PCA also showed reduced food intake and decreased energy expenditure through indirect calorimetry by measuring oxygen consumption with an open-flow respirometric system. We conclude that experimental PCA promotes an angiogenic state in the liver to confront the altered blood flow by reducing the prooxidant reactions associated with lower metabolic rate, along with significant reduction of mitochondrial content, but without a clear hepatic dysfunction.