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

Abstract

SUMMARYObjective: 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 (Ab), 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 reversetranscription 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 Ab, bradykinin, and antigenic peptides. These accumulations could be related to hippocampal inflammation observed in TLE subjects.

Implication of the Kallikrein-Kinin system in neurological disorders: Quest for potential biomarkers and mechanisms

“…These findings were reiterated in human patients with TLE (Perosa, Arganaraz et al 2007). Recently, thimet oligopeptidase (TOP), a metalloprotease whose substrates include BK, was found to be decreased in levels and activity in TLE patients compared to controls, thus potentially explaining the increase in KKS activation due to the low kininase TOP activity (Simoes, Visniauskas et al 2014). More specifically, kinin B1R was considered to have a pro-convulsant role, as its absence reduced hippocampal cell death and mossy fiber sprouting, while the kinin B2R played an anticonvulsant role with an opposite effect on epileptogenesis (Adolfo Arganaraz, Regina Perosa et al 2004).…”

Single amyloid‐beta injection exacerbates 4‐aminopyridine‐induced seizures and changes synaptic coupling in the hippocampus

“…On the other hand, it is reflected by patients with late‐onset epilepsy of unknown origin, exhibiting changes in Aβ levels in the cerebrospinal fluid and abnormal Aβ accumulation in the brain (Costa et al, ). Furthermore, tissue obtained from “temporal lobe epilepsy” patients exhibits Aβ accumulation in senile plaques (Mackenzie & Miller, ) and reduced levels of Aβ‐degrading enzymes in the hippocampus (Simoes et al, ), which support a putative mechanistic relationship between epilepsy and AD through Aβ accumulation. In agreement with this proposal, transgenic AD animal models that overproduce Aβ exhibit spontaneous epileptiform seizures (Minkeviciene et al, ; Palop et al, ; Palop & Mucke, ; Verret et al, ; Ziyatdinova et al, ) and show a reduced threshold for convulsions (Del Vecchio, Gold, Novick, Wong, & Hyde, ).…”

Sleep deprivation changes thimet oligopeptidase (THOP1) expression and activity in rat brain

“…Moreover, processing of neurotensin and opioid peptides by THOP1 emphasizes the importance of peptidases in the control of neuroendocrine and immunological systems. According to Simões and collaborators (2014), THOP1 levels are reduced in both the hippocampus of epileptic patients and in animal models of epilepsy, which effect is potentially related to the accumulation of inflammatory peptides in this area of the brain [19]. However, in vivo demonstration that THOP1 is required to metabolize neuropeptides and to modulate the nociception, immunological, and endocrine systems remains elusive.…”