Effect of a Novel Prolyl Endopeptidase Inhibitor, JTP‐4819, on Prolyl Endopeptidase Activity and Substance P‐ and Arginine‐Vasopressin‐Like Immunoreactivity in the Brains of Aged Rats

Abstract

The effects of a novel prolyl endopeptidase (PEP) inhibitor, (S)‐2‐[[(S)‐2‐(hydroxyacetyl)‐1‐pyrrolidinyl]carbonyl]‐N‐(phenylmethyl)‐1‐pyrrolidinecarboxamide (JTP‐4819), on the PEP activity in the brain and on the contents of substance P (SP)‐ and arginine‐vasopressin (AVP)‐like immunoreactivity (LI) in the cerebral cortex and hippocampus of young and aged rats were investigated using enzyme immunoassay. JTP‐4819 exhibited a concentration‐dependent in vitro inhibitory action on PEP activity in the brains of both young and aged rats, with IC50 values of ∼0.7 and 0.8 nM, respectively. A single dose of JTP‐4819 (3 mg/kg, p.o.) increased the SPLI content in the cerebral cortex but not the hippocampus of aged rats (23–24 months old). In addition, repeated administration of JTP‐4819 (1 mg/kg, p.o., for 21 days) increased the SPLI content in the cerebral cortex and restored the SPLI content in the hippocampus, which had decreased with aging. In contrast, single (1 mg/kg, p.o.) and repeated (1 mg/kg, p.o., for 21 days) administration of JTP‐4819 only tended to increase the AVPLI content of the hippocampus and cerebral cortex in aged rats, respectively. These results indicate that JTP‐4819 increases the cerebral and hippocampal SPLI content in aged rats by inhibiting the action of PEP.

Peptidomics of the Prolyl Peptidases

“…These studies integrate pharmacological inhibition of Prep with postmortem measurements of peptide levels in the central nervous system. The most common method for measuring peptide levels has been to use antibody-based approaches such as immunoassays to detect and quantify changes in levels of specific peptides as a function of Prep inhibition (19)(20)(21). Because immunoassays are necessarily targeted experiments, they are used to test hypotheses, but cannot uncover unknown or unanticipated substrates.…”

“…Differences in ion abundance between the two samples revealed Prep-regulated peptides, including substrates and products of the enzyme. c The identification of natural substrates, such as Hspa12a (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), revealed that Prep can show cleavage site selectivity between two proline amino acids, which would not have been predicted based on the known substrate selectivity of Prep. d Prep also showed a length dependence, preferring shorter substrates, which allows it to cleave the degradation fragment of CGRP, CGRP(20-37), without cleaving the bioactive species CGRP any proline in a peptide can be found in the in vivo data.…”

“…Interestingly, several of these experiments suggested that Prep inhibition would lead to improved cognitive function in mammals, which was later verified (15)(16)(17)(18). However, the underlying mechanism for this improvement is still under investigation because some of the Prep substrates predicted to be responsible for this effect were unaffected, or only modestly affected, upon Prep inhibition (19)(20)(21).…”

A 914-bp promoter is sufficient to reproduce the endogenous prolyl oligopeptidase gene localization in the mouse placenta if not subject to position effect

“…POP is known to be a multifunctional protein and has been reported to play some roles in the degradation of hormones and neuropeptides (Mentlein, 1988;Wilk, 1983), learning and memory (Miura et al, 1997;Shishido et al, 1998;Toide et al, 1995;Yoshimoto et al, 1987), cell signaling (Williams et al, 1999), cell differentiation (Hannula et al, 2011;Ohtsuki et al, 1994), sperm motility (Kimura et al, 2002;Yoshida et al, 1999), obesity Warden et al, 2009), and so on. POP has also attracted attention as a therapeutic target because it is possibly involved in several diseases such as bipolar disorder, Alzheimer's disease, and cancer (García-Horsman et al, 2007;Myöhänen et al, 2009;Williams, 2004).…”

Vers de nouvelles cibles thérapeutiques pour les psychoses maniaco-dépressives?

“…Ces résultats démontrent que cette protéase à sérine, de manière tout à fait inattendue, pourrait intervenir dans le cycle des phospho-inositides chez Dictyostelium. Bien que la fonction physiologique de la POP soit encore mal connue, des études entreprises chez les rongeurs ont montré que cette endopeptidase contribue à l'inactivation des neuropeptides dans le système nerveux central [8]. Parallèlement, divers travaux suggèrent que la POP pourrait être impliquée dans certains troubles de l'humeur.…”