title: 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: BACKGROUND
  Liver 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.
  
  
  METHODS
  PREP 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Real-time Imaging Laboratory, Divisions of Pharmacology and Toxicology and Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, PO Box 56, Helsinki, 00014, Finland. joffrelaranga@msn.com.
authors.forename: Jofre
authors.initials: J
authors.lastname: Tenorio-Laranga
authors.affiliation: Fundación Investigación Hospital Clínico Universitario, INCLIVA, Valencia, Spain. Carmina.Montoliu@uv.es.
authors.forename: Carmina
authors.initials: C
authors.lastname: Montoliu
authors.affiliation: Fundación Investigación Hospital Clínico Universitario, INCLIVA, Valencia, Spain. urios_amp@gva.es.
authors.forename: Amparo
authors.initials: A
authors.lastname: Urios
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Avd.Autopista del Saler 16, 46012, Valencia, Spain. vhernandez@cipf.es.
authors.forename: Vicente
authors.initials: V
authors.lastname: Hernandez-Rabaza
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Avd.Autopista del Saler 16, 46012, Valencia, Spain. hahabrach@cipf.es.
authors.forename: Hanan
authors.initials: H
authors.lastname: Ahabrach
authors.affiliation: Real-time Imaging Laboratory, Divisions of Pharmacology and Toxicology and Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, PO Box 56, Helsinki, 00014, Finland. Arturo.Garcia@helsinki.fi.
authors.forename: J Arturo
authors.initials: JA
authors.lastname: García-Horsman
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Avd.Autopista del Saler 16, 46012, Valencia, Spain. vfelipo@cipf.es.
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001921:Brain / Q000201:enzymology; D006152:Cyclic GMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000150:complications*; D006501:Hepatic Encephalopathy / Q000188:drug therapy / Q000209:etiology*; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use; D017093:Liver Failure / Q000209:etiology / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D011167:Portacaval Shunt, Surgical / Q000009:adverse effects; D000085822:Prolyl Oligopeptidases; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism*; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy / Q000209:etiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D009569:Nitric Oxide; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D006152:Cyclic GMP; D007052:Ibuprofen