Expression and activity of thimet oligopeptidase (TOP) are modified in the hippocampus of subjects with temporal lobe epilepsy (TLE)

• Published in: Epilepsia (Copenhagen) Vol. 55; no. 5; pp. 754 - 762
• Main Authors: Simões, Priscila Santos Rodrigues, Visniauskas, Bruna, Perosa, Sandra Regina, Yacubian, Elza Márcia Targas, Centeno, Ricardo, Canzian, Mauro, Lopes‐Cendes, Iscia, Maurer Morelli, Claudia Vianna, Carrete, Henrique, Cavalheiro, Esper Abrão, Tufik, Sergio, Chagas, Jair Ribeiro, Naffah Mazzacoratti, Maria da Graça
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-05-2014
• Subjects: Adult; Animals; Anterior Temporal Lobectomy; Disease Models, Animal; Epilepsy; Epilepsy, Temporal Lobe - genetics; Epilepsy, Temporal Lobe - pathology; Epilepsy, Temporal Lobe - surgery; Female; Gene Expression Regulation, Enzymologic - genetics; Hippocampus - pathology; Hippocampus - surgery; Humans; Injections, Intraperitoneal; Male; Mesial sclerosis; Metalloendopeptidases - genetics; Middle Aged; Peptides; Pilocarpine; Rats; RNA, Messenger - genetics; Rodents; Sclerosis; Temporal Lobe - pathology; Temporal lobe epilepsy; Thimet oligopeptidase; Young Adult; Mesial sclerosis; Temporal lobe epilepsy; Thimet oligopeptidase; Pilocarpine
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.12606

Summary
Objective
Thimet oligopeptidase (TOP) is a metalloprotease that has been associated with peptide processing in several nervous system structures, and its substrates include several peptides such as bradykinin, amyloid beta (Aβ), and major histocompatibility complex (MHC) class I molecules. As shown previously by our research group, patients with temporal lobe epilepsy (TLE) have a high level of kinin receptors as well as kallikrein, a kinin‐releasing enzyme, in the hippocampus.
Methods
In this study, we evaluated the expression, distribution, and activity of TOP in the hippocampus of patients with TLE and autopsy‐control tissues, through reverse‐transcription polymerase chain reaction (RT‐PCR), enzymatic activity, Western blot, and immunohistochemistry. In addition, hippocampi of rats were analyzed using the pilocarpine‐induced epilepsy model. Animals were grouped according to the epilepsy phases defined in the model as acute, silent, and chronic.
Results
Increased TOP mRNA expression, decreased protein levels and enzymatic activity were observed in tissues of patients, compared to control samples. In addition, decreased TOP distribution was also visualized by immunohistochemistry. Similar results were observed in tissues of rats during the acute phase of epilepsy model. However, increased TOP mRNA expression and no changes in immunoreactivity were found in the silent phase, whereas increased TOP mRNA expression and increased enzymatic activity were observed in the chronic phase.
Significance
The results show that these alterations could be related to a failure in the mechanisms involved in clearance of inflammatory peptides in the hippocampus, suggesting an accumulation of potentially harmful substances in nervous tissue such as Aβ, bradykinin, and antigenic peptides. These accumulations could be related to hippocampal inflammation observed in TLE subjects.