Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on neuropeptide metabolism in the rat brain

Toide, Katsuo; Fujiwara, Takako; Iwamoto, Yohko; Shinoda, Masahiko; Okamiya, Kazuhiro; Kato, Takeshi

doi:10.1007/bf00168640

Cited by 49 publications

(36 citation statements)

References 46 publications

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“…These findings do not support some earlier results [9,32], but we want to point out that a repeated treatment with S 17092 has also failed to increase the levels of brain neuropeptides [9]. A single oral administration of JTP-4819 did not increase thyrotropin-releasing hormone levels in rat cerebral cortex [33]. In aged rats, single administration of JTP-4819 failed to increase hippocampal substance P levels, and both cortical and hippocampal arginine-vasopressin levels remained unaffected after single or repeated JTP-4819 dosing [32].…”

Section: Discussioncontrasting

confidence: 82%

Beneficial Effect of Prolyl Oligopeptidase Inhibition on Spatial Memory in Young but Not in Old Scopolamine‐Treated Rats

Jalkanen¹,

Puttonen²,

Venäläinen³

et al. 2006

Basic Clin Pharma Tox

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The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP-2047 on spatial memory of young (3-monthold) and old (8-to 9-month-old) scopolamine-treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats. In addition, inositol-1,4,5-trisphosphate (IP 3 ) levels were assayed in rat cortex and hippocampus after effective 2.5-day POP inhibition. KYP-2047 (1 or 5 mg/kg 30 min. before daily testing) dose-dependently improved the escape performance (i.e. latency to find the hidden platform and swimming path length) of the young but not the old rats in the water maze. POP inhibition had no consistent effect on substance P levels in cortex, hippocampus or hypothalamus, and only a modest increase in neurotensin concentration was observed in the hypothalamus after a single dose of KYP-2047. Moreover, IP 3 concentrations remained unaffected in cortex and hippocampus after POP inhibition. In conclusion, the behavioural data support the earlier findings of the promnesic action of POP inhibitors, but the mechanism of the memory-enhancing action remains unclear.In addition to the cholinergic neurones, many neuropeptides may play a role in cognitive functions such as learning and memory. These peptides include vasopressin, neurotensin, oxytocin, substance P and bradykinin [1,2]. A common feature of the above-mentioned promnesic neuropeptides is their sensitivity to prolyl oligopeptidase (POP, EC 3.4.21.26), also known as prolyl endopeptidase [1]. POP is a member of the serine protease family that hydrolyses peptide bonds at the carboxy terminal of  -proline. The effects of POP in memory disorders are somewhat conflicting. On one hand, some findings suggest that a decrease in POP activity is characteristic of a generalized process of neurodegeneration, including Alzheimer's disease and dementia [3]. However, for example in Alzheimer's disease, the changes in POP activities depend on which brain areas are being investigated. In cerebral cortex, a reduction in POP activity has been observed, whereas in occipital cortex, the POP activity seems to increase [4]. It has been proposed but not proved that these alterations in POP activity in Alzheimer's disease and dementia account for some of the observed changes in neuropeptide levels. In Alzheimer's disease, vasopressin and substance P levels decrease in cortical areas and hippocampus [5], areas implicated in cognitive processes. Furthermore, increased levels of neuropeptides have been shown to improve cognitive function in experimental animals [6,7].These observations would seem to indicate that manipulations of POP activity and its secondary effects on neuropeptide levels could represent a potential therapeutic target for treatment of cognitive disorders. Several POP inhibitors have been studied in animals. Studies with rats have demonstrated memo...

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Section: Discussioncontrasting

confidence: 82%

Beneficial Effect of Prolyl Oligopeptidase Inhibition on Spatial Memory in Young but Not in Old Scopolamine‐Treated Rats

Jalkanen¹,

Puttonen²,

Venäläinen³

et al. 2006

Basic Clin Pharma Tox

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“…It is now firmly established that PEP plays a pivotal role in the catabolism of a variety of biologically active neuropeptides, notably those that appear to be implicated in memory and learning processes (Toide et al, 1996;Bellemère et al, 2003). Concurrently, it has been shown that selective PEP inhibitors exert antiamnesic effects and improve cognitive performances (Yoshimoto et al, 1987;Toide et al, 1995a), supporting the notion that PEP could be involved in the physiopathology of neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 92%

“…In vitro studies have shown that PEP can actually cleave several neuropeptides, such as substance P (SP), ␣-melanocyte-stimulating hormone (␣-MSH), arginine-vasopressin (AVP), thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), neurotensin, and oxytocin, suggesting that PEP may contribute to peptide breakdown in the central nervous system (CNS; Taylor and Dixon, 1980;Wilk, 1983). In support of this hypothesis, it has been found that administration of PEP inhibitors provokes a significant increase in SP, ␣-MSH, AVP, and TRH concentrations in the rat brain (Toide et al, 1996;Bellemère et al, 2003).…”

mentioning

confidence: 82%

Localization of the mRNA encoding prolyl endopeptidase in the rat brain and pituitary

Bellemère

Vaudry

Mounien

et al. 2004

J of Comparative Neurology

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Prolyl endopeptidase (EC 3.4.21.26, PEP), a serine protease that hydrolyzes peptides at the carboxyl side of proline residues, is involved in the breakdown of several proline-containing neuropeptides and, thus, may contribute to the regulation of behavioral activities. In this study, the distribution of PEP mRNA was investigated in the central nervous system and pituitary of rat by means of quantitative reverse transcriptase-polymerase chain reaction analysis and in situ hybridization histochemistry. High densities of PEP transcripts were found in cerebellar Purkinje and granule cells, within most hypothalamic nuclei, in pyramidal neurons of the Ammon's horn, in granule cells of the dentate gyrus, and within the basolateral complex of the amygdala. Moderate levels of PEP mRNA were observed in layers 3-5 of the cerebral cortex, the anterior thalamic group, the septal region, the substantia nigra, the magnocellular neurons of the red nucleus, and the motor nuclei of the cranial nerves. Low concentrations of PEP mRNA were detected in the deep mesencephalic nuclei, the reticular formation, the pretectum, and the tectum. A high density of PEP mRNA was found in the intermediate and the anterior lobes of the pituitary, while the neural lobe was devoid of labeling. In several brain regions, the distribution pattern of PEP mRNA overlapped that of various neuropeptide receptors, suggesting that PEP is actually involved in the inactivation of regulatory neuropeptides.

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“…POP is implicated in the metabolism of peptide hormones and neuropeptides [2][3][4] although some of the previously identified neuropeptide substrates do not appear to be hydrolyzed in vivo upon closer inspection [5]. Specific inhibitors have been shown to relieve scopolamine-induced amnesia [6], to ameliorate memory loss caused by age, brain lesions, or amnesic drugs [7,8] and were neuroprotective under various conditions [9][10][11], resulting in significant pharmaceutical and academic interest. It was reported that POP has roles in the phosphoinositide cycle [12][13][14], intracellular transport [15], cellular differentiation [16], inflammation [17], angiogenesis [18], and cancer development [19].…”

Section: Introductionmentioning

confidence: 99%

The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity

Szeltner

Juhász

Szamosi

et al. 2013

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Prolyl oligopeptidase (POP) has emerged as a drug target for neurological diseases. A flexible loop structure comprising loop A (res. 189-209) and loop B (res. 577-608) at the domain interface is implicated in substrate entry to the active site. Here we determined the kinetic and structural properties of POP with mutations in loop A, loop B and in two additional flexible loops. POP lacking loop A proved to be an inefficient enzyme as did POP with a mutation in loop B (T590C). Both constructs displayed an altered substrate preference profile. Ligand binding become markedly degraded. Conversely, the T202C mutation increased the flexibility of loop A, enhancing the catalytic efficiency beyond that of the native enzyme. The T590C mutation in loop B increased the preference for shorter peptides, indicating a role in substrate gating. Loop A and the His loop housing the catalytic histidine are disordered in the H680A mutant crystal structure, implying coordinated structural dynamics of these loops. A 17-mer peptide could not inhibit variants possessing malfunctioning loop A. This substrate may bind non-productively to an exosite involving loop A or to an open enzyme form. Biophysical studies suggest that mammalian POP resides in a predominantly closed conformational state, especially at physiological conditions. The flexible loop A, loop B and His loop system at the active site is the main regulator of substrate gating and specificity and represents a new inhibitor target.

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Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on neuropeptide metabolism in the rat brain

Cited by 49 publications

References 46 publications

Beneficial Effect of Prolyl Oligopeptidase Inhibition on Spatial Memory in Young but Not in Old Scopolamine‐Treated Rats

Beneficial Effect of Prolyl Oligopeptidase Inhibition on Spatial Memory in Young but Not in Old Scopolamine‐Treated Rats

Localization of the mRNA encoding prolyl endopeptidase in the rat brain and pituitary

The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity

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