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Role of prolyl oligopeptidase in neuroinflammation and novel therapeutic use of specific POP inhibitors

Final Report Summary - POP IN INFLAMMATION (Role of prolyl oligopeptidase in neuroinflammation and novel therapeutic use of specific POP inhibitors)

The general aim of the project was to contribute to the knowledge in the molecular mechanism involving the enzyme prolyl oligopeptidase (POP) and its inhibitor in the frame of inflammation and neurodegeneration. The project was specially design to achieve the main goal from different perspectives and approaches, ensuring an efficient contribution to new therapeutic approaches for neurodegeneration and neuroinflammation. It was discovered that circulating prolyl oligopeptidase is significantly decreased in multiple sclerosis (MS) but only in the forms where there is an important inflammatory component.

Of importance, it was seen that in the MS pre-diagnosis group with the clinically isolated syndrome (patients which have experienced a first neurologic episode that lasts at least 24 hours, and is caused by inflammation/demyelination in one or more sites in the central nervous system) the levels of prolyl oligopeptidase were already decreased which might set this peptidase as a pre-diagnosis of MS. In the research aimed to investigate the molecular mechanisms of the changes observed and the link with the disease, it was discovered that the homeostasis of the cell signalling and peptide levels are disrupted, suggested by the concomitant changes on protease endogenous inhibition (alpha-2-macroglobulin) and the effect of prolyl oligopeptidase in the excitability of immune related cells as neural glial and peripheral macrophages. This ins a new avenue in the research in inflammatory diseases.

The work performed since the beginning of the project include:

-Clinical studies evaluating different blood markers and POP activity from human patients suffering different forms of multiple sclerosis. In addition, we also performed the same studies in another disease model, hepatic encephalopathy.
-Characterization and identification of a protein altered in multiple sclerosis and able to inhibit POP in vitro.
-Construction of an affinity chromatography containing POP inhibitors in order to detect possible off-targets for the POP inhibitors.
-Testing the effect of POP inhibitors on the activation of the MAPK signaling pathway under different stimulus in macrophages and neuroblastoma cell lines.
-Administration of POP inhibitors to 6-hydroxydopamine-lesioned rats (neurodegenerative model) and to mice treated with lipopolysaccharide (inflammatory model).

The main results obtained during this project can be summarized in the following bullets:

- POP activity is reduced in pathologies which hold a strong inflammatory component such as the inflammatory forms of multiple sclerosis and liver cirrhosis.
-POP is involved in specific signalling pathways regulating immune responses.

We believed that the results arouse from that project could lead to the development of new therapeutic avenues for the treatment of autoimmune pathologies.