Effect of a Novel Prolyl Endopeptidase Inhibitor, JTP-4819, on Spatial Memory and Central Cholinergic Neurons in Aged Rats

Toide, Katsuo; Shinoda, Masahiko; Fujiwara, Takako; Iwamoto, Yohko

doi:10.1016/s0091-3057(96)00238-9

Cited by 59 publications

(44 citation statements)

References 46 publications

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“…The molecular formula was shown to be C 15 13 C-NMR spectra of 3 corroborated the presence of three methyl, three methylene, four methine and five quaternary carbons. The signal at d 194.2 was due to the conjugated carbonyl.…”

Section: Resultsmentioning

confidence: 84%

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Enzyme Inhibitory Constituents from Duranta repens.

et al. 2002

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The genus Duranta (Verbenaceae) comprises about 35 species which are distributed in tropical and sub-tropical regions. The literature survey revealed that very little phytochemical work has been carried out on the genus Duranta, and only some steroids, 1) triterpenes 2) and iridoids 3) have so far been reported. Duranta repens LINN. is widely distributed in northern parts of Pakistan and finds various medicinal uses in the indigenous system of medicine. The fruits of this plant afford a medicine for the treatment of malaria.4) The methanolic extract also shows insecticidal and antifeedant properties.5) Previously, diterpenoids and flavonoids have been reported. 6) Our preliminary pharmacological screening of the methanolic extract revealed inhibitory activity against both thrombin and prolyl endopeptidase enzymes. This prompted us to carry out the phytochemical studies on this plant. We now report the isolation and structure elucidation of the two new isoprenylated flavonoids 1 and 2, and of an isoprenylated acetophenone derivative 3, along with the known compounds, 5-hydroxy-3,6,7,4Ј-tetramethoxyflavone (4), 7) rosenonolactone (5), 8) 6,7-dimethoxycoumarin (6), 9) 5a,8a-epidioxyergosta-6,22-dien-3b-ol (7) 10) and 5a,8a-epidioxyergosta-6,9(11),22-trien-3b-ol (8) 11) isolated for the first time from this species.Prolyl endopeptidase (PEP, EC 3.4.21.26) is the only serine protease which is known to cleave a peptide substrate in the C-terminal side of a proline residue.12) Prolyl endopeptidase has been suggested to play an important role in the biological regulation of peptide hormones such as vasopresssin, oxytocin, substance P, angiotensin and others.13) Moreover alterations of PEP enzyme level and activity seems to be associated with several health disorders such as Alzheimer's disease, depression, mania, thrombosis, AIDS and cancer. 14)Specific inhibitors of PEP are expected to have anti-amnesic effects. Many PEP inhibitors have been synthesized as candidates for the treatment of neuropathological disorders. 15) In the course of this work we have evaluated compounds 1-5 for their enzyme inhibiting activity. The compounds 1 and 2 showed strong inhibitory activity against PEP while 3-5 showed moderate activity. Moreover 4 and 5 also showed strong inhibitory activity against thrombin. The compounds 6-8 did not show enzyme inhibiting activity. April 2002Chem. Pharm. Bull. 50(4) 515-518 (2002) 515 * To whom correspondence should be addressed. Karachi-75270, Pakistan. Received November 26, 2001; accepted January 22, 2002 Isoprenylated flavonoids 5,7-dihydroxy-3- (2-hydroxy-3-methyl-3-butenyl)-3,6,4-trimethoxyflavone (1), 3,7-dihydroxy-3-(2-hydroxy-3-methyl-3-butenyl)-5,6,4-trimethoxyflavone (2) and an isoprenylated acetophenone derivative (3) have been isolated from Duranta repens along with known compounds, 5-hydroxy-3,6,7,4-tetramethoxyflavone (4), rosenonolactone (5), 6,7-dimethoxycoumarin (6), 5a a,8a a-epidioxyergosta-6,22-dien-3b b-ol (7) and 5a a,8a a-epidioxyergosta-6,9(11),22-trien-3b b-ol (8), isolat...

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Section: Resultsmentioning

confidence: 84%

“…Many PEP inhibitors have been synthesized as candidates for the treatment of neuropathological disorders. 15) In the course of this work we have evaluated compounds 1-5 for their enzyme inhibiting activity. The compounds 1 and 2 showed strong inhibitory activity against PEP while 3-5 showed moderate activity.…”

Section: )mentioning

confidence: 99%

Enzyme Inhibitory Constituents from Duranta repens.

et al. 2002

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“…PREP is widely distributed in the brain (Irazusta et al, 2002;Myöhänen et al, 2007Myöhänen et al, , 2008 and increased activity of PREP has been associated with cell death processes in various neurodegenerative diseases, including Alzheimer's and Parkinson's diseases (Brandt et al, 2008;Mantle et al, 1996). PREP is believed to act in the extracellular space with involvement in the maturation and degradation of peptide hormones and neuropeptides (Bellemere et al, 2004;Cunningham and O'Connor, 1997;Shishido et al, 1999), which has been proposed to be the mechanism underlying some beneficial effects of PREP inhibitors in animal memory models (Shishido et al, 1998;Toide et al, 1997;Yoshimoto et al, 1987) and in aged mice (Kato et al, 1997). Besides its extracellular action, PREP has been shown to act intracellularly and important roles of PREP have been demonstrated in signaling pathways or in transport and secretion of proteins and peptides associated with neurodegeneration (Brandt et al, 2008;Di Daniel et al, 2009;Rossner et al, 2005;Savolainen et al, 2015;Schulz et al, 2002Schulz et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro

Jaako

Waniek

Parik

et al. 2016

Journal of Cell Science

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Membrane-associated glycoprotein neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) play an important role in brain plasticity by regulating cell-cell interactions. Here, we demonstrate that the cytosolic serine protease prolyl endopeptidase (PREP) is able to regulate NCAM and PSA-NCAM. Using a SH-SY5Y neuroblastoma cell line with stable overexpression of PREP, we found a remarkable loss of PSA-NCAM, reduced levels of NCAM180 and NCAM140 protein species, and a significant increase in the NCAM immunoreactive band migrating at an apparent molecular weight of 120 kDa in PREP-overexpressing cells. Moreover, increased levels of NCAM fragments were found in the concentrated medium derived from PREP-overexpressing cells. PREP overexpression selectively induced an activation of matrix metalloproteinase-9 (MMP-9), which could be involved in the observed degradation of NCAM, as MMP-9 neutralization reduced the levels of NCAM fragments in cell culture medium. We propose that increased PREP levels promote epidermal growth factor receptor (EGFR) signaling, which in turn activates MMP-9. In conclusion, our findings provide evidence for newlydiscovered roles for PREP in mechanisms regulating cellular plasticity through NCAM and PSA-NCAM.

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“…[11] Furthermore, POP inhibition reverses scopolamine-induced amnesia in rats [12] and improves cognition in MTPT (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated primates [13] and aged rats. [14] Although the mechanism by which POP regulates IP 3 levels remains to be clarified, the mentioned data strongly suggest that the development of selective POP inhibitors would be beneficial in the treatment of patients with cognitive disorders. [15] In contrast to POP, DPP IV is a glycoprotein that is present on the cell surface of numerous tissues, it hydrolyzes peptides of up to about 80 residues long and is catalytically active as a homodimer.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous ¹⁹F NMR Screening of Prolyl Oligopeptidase and Dipeptidyl Peptidase IV Inhibitors

2010

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Prolyl oligopeptidase (POP) and dipeptidyl peptidase IV (DPP IV) are serine proteases that belong to the same family of enzymes. These peptidases are relevant because of their association with the pathophysiology of serious illnesses, such as type 2 diabetes (DPP IV), and those related to cognitive disorders (POP). Several NMR-based screening methods are being used to find and validate new hit scaffolds. In particular, (19)F NMR-based screening methods have proven to be powerful tools for the discovery and development of new inhibitors. Here we present an accurate and reliable (19)F NMR-based simultaneous assay that is used to screen for new selective POP and DPP IV inhibitors in compound mixtures. This activity assay consists of the simultaneous performance of POP and DPP-IV (19)F NMR activity assays in the presence of their fluorine-containing substrates. Furthermore, the assays were conducted in the presence of 0.01 % v/v of Triton X-100, which is a detergent that disrupts micelle formation, thereby preventing unspecific aggregate-based inhibition. Finally, this (19)F NMR methodology was applied to screen for ligands in plant extracts. Our results indicate that this method allows the simultaneous and accurate identification of selective POP and DPP IV inhibitors in these compound mixtures.

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Effect of a Novel Prolyl Endopeptidase Inhibitor, JTP-4819, on Spatial Memory and Central Cholinergic Neurons in Aged Rats

Cited by 59 publications

References 46 publications

Enzyme Inhibitory Constituents from Duranta repens.

Enzyme Inhibitory Constituents from Duranta repens.

Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro

Simultaneous ¹⁹F NMR Screening of Prolyl Oligopeptidase and Dipeptidyl Peptidase IV Inhibitors

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Effect of a Novel Prolyl Endopeptidase Inhibitor, JTP-4819, on Spatial Memory and Central Cholinergic Neurons in Aged Rats

Cited by 59 publications

References 46 publications

Enzyme Inhibitory Constituents from Duranta repens.

Enzyme Inhibitory Constituents from Duranta repens.

Prolyl endopeptidase is involved in the degradation of neural cell adhesion molecules in vitro

Simultaneous 19F NMR Screening of Prolyl Oligopeptidase and Dipeptidyl Peptidase IV Inhibitors

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Simultaneous ¹⁹F NMR Screening of Prolyl Oligopeptidase and Dipeptidyl Peptidase IV Inhibitors