A Novel Prolyl Endopeptidase Inhibitor, JTP-4819 - Its Behavioral and Neurochemical Properties for the Treatment of Alzheimer's Disease

Toide, Katsuo; Shinoda, Masahiko; Miyazaki, Akira

doi:10.1515/revneuro.1998.9.1.17

Cited by 28 publications

(20 citation statements)

References 72 publications

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“…It has been shown previously that selective PEP inhibitors suppress in vitro ␤-amyloid protein formation (Shinoda et al, 1997) and prevent in vivo amyloid deposition in the hippocampus of senescence-accelerated mice (Kato et al, 1997). Thus, the present data showing that the cerebral cortex and hippocampus are enriched with PEP mRNA support the view that PEP inhibitors may represent a new therapeutic approach for the treatment of Alzheimer's disease (Kato et al, 1997;Toide et al, 1998).…”

Section: Functional Implicationssupporting

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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Section: Functional Implicationssupporting

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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“…40) Previous studies on inhibitors of prolyl endopeptidase focused primarily on proline peptides and mimetics. 41) To the best of our knowledge, the inhibitory activities of procyanidins on prolyl endopeptidase have not been reported.…”

Section: Protease Inhibitory Activitiesmentioning

confidence: 99%

Polyphenolic Content and Physiological Activities of Chinese Hawthorn Extracts

Cui

Nakamura

Tian

et al. 2006

Bioscience, Biotechnology, and Biochemistry

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Hawthorn polyphenol (HP) was prepared by ethyl acetate treatment of the ethanol extract (HE) of Chinese hawthorn fruit. The concentrations of 15 polyphenols in the HP, HE, extraction residue (HJ), and a hawthorn leaf extract (HF) were determined by HPLC. For HP, the total content of the 15 polyphenols was 21.4%, comprised of 19.7% of procyanidins, 1.21% of chlorogenic acid, and 0.48% of flavonoids, compared to 2.55% for the HE. The yields of procyanidin monomer, dimer, trimer, tetramer, and pentamer were 50.5%, 30.3%, 23.0%, 14.6%, and 12.5% respectively, and the mean degree of polymerization was reduced to 1.39 (HP) from 1.65 (HE). Seven different physiological actions of the four extracts were investigated. The HP showed strong O 2 À and OH scavenging capacities (IC 50 values of 6.3 g/ml and 1.1 g/ml respectively), as well as selective prolyl endopeptidase inhibition (IC 50 of 60 g/ml). The active constituents appeared to be procyanidins.Key words: Crataegus pinnatifida; HPLC; procyanidin; antioxidant; free radicalsIn Europe, standardized extracts of the leaves and flowers of Crataegus oxyacantha and Crataegus monogyna are used in the therapy for moderate (NYHA II) congestive heart failure. 1,2) These extracts exert several pharmacological and clinical effects, such as antiischemia/reperfusion-injury, anti-arrhythmic, hypolipidemic, and hypotensive effects. 1,2) Flavonoids and procyanidins are considered to be the two main active constituents. 2) Species of Chinese hawthorn, particularly Crataegus pinnatifida and Crataegus pinnatifida Bge. var. major NE Br., have also been used as herbal medicines. 2,3) Studies indicate that Chinese hawthorn extracts have beneficial effects, such as antioxidant, 4,5) anti-inflammatory, 6) and hypolipidemic effects, 7) as well as protective effects on the brain and vascular endothelium 8,9) and endothelium-dependent relaxation. 10) Recently, we analyzed 37 major cultivars of Chinese hawthorn using high performance liquid chromatography (HPLC), and found that procyanidins, which were present in high concentrations, were the main phenolic active constituents in these fruits. 11) In general, the hawthorn found in China is an edible fruit that is popular for its special acidic taste. It is bigger than its European counterpart. Since the content of organic acid in Chinese hawthorn fruits can be up to 5% (fresh weight), they are used to produce various foods, such as jams, jellies, juices, tinned foods, wines, and various sweet foods. However, the high sugar content of these fruits counteracts the benefits of polyphenols for consumers of advanced age or for those who suffer from hypertension, cardiovascular disease, or diabetes. Hence, it is desirable to separate the polyphenol and sugar components. Previously, hawthorn extract (HE) for medical applications were ethanol-extracted from the dried fruit of the Chinese hawthorn. 12) These crude extracts contain many undesirable substances, such as carbohydrates, organic acids, and moisture, which not only reduce the concentration of acti...

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“…Speculations about these physiological roles of POP have gained some support from neuroprotective and cognition-enhancing effects of POP inhibitors [20,21,22]. In some drug- or lesion-induced amnesia models and in aged rodents, POP inhibitors have been able to reverse memory loss, although the results are not convincing [14].…”

Section: Introductionmentioning

confidence: 99%

Sequential Expression, Activity and Nuclear Localization of Prolyl Oligopeptidase Protein in the Developing Rat Brain

Hannula¹,

Männistö²,

Myöhänen³

2010

Dev Neurosci

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Prolyl oligopeptidase (POP) is a serine protease that hydrolyzes peptides shorter than 30-mer. Some evidence has recently been obtained that POP can generate protein-protein interactions and therefore participate in various physiological and pathological events. Several studies have reported that POP may be involved in neurogenesis since its activity increases during development and can be found in the nucleus of proliferating tissues. In cell cultures, POP has been shown to be localized in the nucleus, but only early in the development, since during maturation it is moved to the cytosol. We have now studied for the first time the expression of POP protein, its enzymatic activity and nuclear localization in vivo in the developing rat brain. We observed that enzymatic activity of POP is highest on embryonic day 18 while the protein amounts reach their peak at birth. Furthermore, POP is located in the nucleus only early in the development but is transferred to the cytosol already before parturition. Our in vivo results confirm the previous cell culture results supporting the role of POP in neurogenesis. A discordance of antenatal protein amounts and enzymatic activities is suggesting a tight regulation of POP activity and possibly even a nonhydrolytic role at that stage.

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A Novel Prolyl Endopeptidase Inhibitor, JTP-4819 - Its Behavioral and Neurochemical Properties for the Treatment of Alzheimer's Disease

Cited by 28 publications

References 72 publications

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

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

Polyphenolic Content and Physiological Activities of Chinese Hawthorn Extracts

Sequential Expression, Activity and Nuclear Localization of Prolyl Oligopeptidase Protein in the Developing Rat Brain

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