The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients

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.

Extracellular prolyl oligopeptidase derived from activated microglia is a potential neuroprotection target

“…Elevated PREP activity has also been detected in the sputum of cystic fibrosis patients and knee synovial fluid of patients with rheumatoid arthritis . Pre‐clinically, extracellular brain PREP activity has been identified in a rat model of neuroinflammation . Thus, the present study raises the possibility that the increased extracellular PREP activity observed in these pathological conditions did originate from the immune cells at the site of inflammation.…”

“…24 Pre-clinically, extracellular brain PREP activity has been identified in a rat model of neuroinflammation. 18 Thus, the present study raises the possibility that the increased extracellular PREP activity observed in these pathological conditions did originate from the immune cells at the site of inflammation. It remains to be clarified why extracellular PREP activity increases specifically in microglial cells during inflammation, but PREP appears to play a role in microglia activation, as PREP knockout mice show a lack of response to LPS at both behavioural and immunohistochemical levels.…”

Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice

“…Cirrhosis is associated with dysbiosis or an altered gut microbiota that potentiates a systemic proinflammatory milieu . This inflammatory environment can potentiate neuroinflammation and brain dysfunction in the setting of hyperammonemia . However, the specific contribution of the gut microbiota toward neuroinflammation and hyperammonemia in cirrhosis is unclear given that ammonia production can also occur through intestinal glutaminase activity in germ‐free (GF) animals .…”

Comparison of the Analgesic Activity of Antiparkinsonian Aminoadamantane Derivatives Amantadine and Hemantane

“…activity in the plasma of rats with rotenone-induced Parkinson's disease to the level representative for intact rats [47]. The activity of the enzyme is known to correlate with the level of proinflammatory interleukins in rat models and in cirrhotic patients [48].…”