Abstract
BackgroundLiver failure in experimental animals or in human cirrhosis elicits neuroinflammation. Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory events in neurodegenerative diseases: PREP protein levels are increased in brain glial cells upon neuroinflammatory insults, but the circulating PREP activity levels are decreased in multiple sclerosis patients in a process probably mediated by bioactive peptides. In this work, we studied the variation of PREP levels upon liver failure and correlated it with several inflammatory markers to conclude on the relation of PREP with systemic and/or neuroinflammation.MethodsPREP enzymatic activity and protein levels measured with immunological techniques were determined in the brain and plasma of rats with portacaval shunt (PCS) and after treatment with ibuprofen. Those results were compared with the levels of PREP measured in plasma from cirrhotic patients with or without minimal hepatic encephalopathy (MHE). Levels of several pro-inflammatory cytokines and those of NO/cGMP homeostasis metabolites were measured in PCS rats and cirrhotic patients to conclude on the role of PREP in inflammation.ResultsIn PCA rats, we found that PREP levels are significantly increased in the hippocampus, striatum and cerebellum, that in the cerebellum the PREP increase was significantly found in the extracellular space and that the levels were restored to those measured in control rats after administration of an anti-inflammatory agent, ibuprofen. In cirrhotic patients, circulatory PREP activity was found to correlate to systemic and neuroinflammatory markers and had a negative correlation with the severity of the disease, although no clear relation to MHE.ConclusionsThese results support the idea that PREP levels could be used as indicators of cirrhosis severity in humans, and using other markers, it might contribute to assessing the level of neuroinflammation in those patients. This work reports, for the first time, that PREP is secreted to the extracellular space in the cerebellum most probably due to glial activation and supports the role of the peptidase in the inflammatory response.
Highlights
Liver failure in experimental animals or in human cirrhosis elicits neuroinflammation
PREP levels are restored to normal upon ibuprofen treatment of portacaval shunt (PCS) rats We have reported that treatment with an antiinflammatory agent, ibuprofen, restores motor function in PCS rats and normalizes glutamate in substantia nigra pars reticulata (SNr) [39]
In this paper, we report that PREP level is increased in the brain of Hepatic encephalopathy (HE) models, and the peptidase is, at least in the cerebellum, secreted out from the cells
Summary
Liver failure in experimental animals or in human cirrhosis elicits neuroinflammation. We studied the variation of PREP levels upon liver failure and correlated it with several inflammatory markers to conclude on the relation of PREP with systemic and/or neuroinflammation. Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome resulting from chronic or acute liver disease; 30–50 % of patients with liver cirrhosis present minimal forms of HE [1]. In patients with minimal HE, cognitive impairment correlates with serum levels of inflammatory cytokines IL-6 and IL-18 [8]. We have shown that neuroinflammation is produced upon mimicking liver failure in rats [5, 6], which models human HE. Anti-inflammatory drugs as ibuprofen [5] or MAPK-p38 inhibitors [9] have shown to restore cognitive function in PCS rats
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