Thyrotrophin-releasing hormone inactivation by human postmortem brain

Griffiths, E.C.; Baris, Charlotte; Visser, Theo J.; Klootwijk, W.

doi:10.1016/0167-0115(85)90009-6

Cited by 28 publications

(8 citation statements)

References 21 publications

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“…An enzyme that hydrolyses peptide bonds at the carboxyl terminus of L-proline residues was first found as an oxytocininactivating enzyme in the human uterus (Walter et al 1971). PEP is present at high levels in the brain (Taylor and Dixon 1980;Yoshimoto et al 1979Yoshimoto et al , 1983Walter et al 1980;Knisatschek and Bauer 1986;Kalwant and Porter 1991), where it may be involved in the metabolism of proline-containing neuropeptides such as substance P (SP), arginine-vasopressin (AVP), and thyrotropin-releasing hormone (TRH) (Wilk 1983;Griffiths et al 1985;Yoshimoto 1991) that are related to learning and memory (De Wied 1984;De Wied et al 1984;Hasen6hrl et al 1990;Huston et al 1993;Schlesinger et al 1983;Taira and Kaneto 1987). PEP is present at high levels in the brain (Taylor and Dixon 1980;Yoshimoto et al 1979Yoshimoto et al , 1983Walter et al 1980;Knisatschek and Bauer 1986;Kalwant and Porter 1991), where it may be involved in the metabolism of proline-containing neuropeptides such as substance P (SP), arginine-vasopressin (AVP), and thyrotropin-releasing hormone (TRH) (Wilk 1983;Griffiths et al 1985;Yoshimoto 1991) that are related to learning and memory (De Wied 1984;De Wied et al 1984;Hasen6hrl et al 1990;Huston et al 1993;Schlesinger et al 1983;Taira and Kaneto 1987).…”

Section: Introductionmentioning

confidence: 99%

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

Toide

Fujiwara

Iwamoto

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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The effect of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl] carbonyl]-N-(phenylmethyl)-1-pyrrolidine-carboxamide (JTP-4819), on neuropeptide metabolism was investigated in the rat brain. JTP-4819 exhibited a strong in vitro inhibitory effect on cortical and hippocampal PEP activity, with the IC50 values being approximately 0.58 +/- 0.02 and 0.61 +/- 0.06 nM, respectively. JTP-4819 also inhibited the in vitro degradation of substance P (SP), arginine-vasopressin (AVP), and thyrotropin-releasing hormone (TRH) by rat brain supernatants, with the IC50 values being respectively 3.4, 2.1, and 1.4 nM in the cerebral cortex and 3.3, 2.8, and 1.9 nM in the hippocampus. Oral administration of JTP-4819 at doses of 1 and 3 mg/kg increased SP-like immunoreactivity (LI) and AVP-LI in the cerebral cortex. JTP-4819 also increased hippocampal SP-LI and AVP-LI at doses of 1 and 3 mg/kg, as well as hippocampal TRH-LI at a dose of 3 mg/kg. These findings suggest that JTP-4819 inhibited the degradation of SP, AVP, and TRH in the rat brain secondary to the inhibition of PEP, and thus increased cortical and hippocampal SP-LI and AVP-LI as well as hippocampal TRH-LI.

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Section: Introductionmentioning

confidence: 99%

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

Toide

Fujiwara

Iwamoto

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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“…All members of the M1 family are aminopeptidases, except for pyroglutamyl peptidase II (PPII, EC 3.4.19.6), a membrane-bound omegapeptidase that catalyzes the inactivation of the neuropeptide thyrotropin-releasing hormone (TRH, ϽGlu-His-Pro-NH 2 ) in the extracellular space (8 -12). TRH is a neurohormone that regulates adenohypophysial secretions and a neurotransmitter with effects on multiple central nervous system functions, including cognition and locomotion (13)(14)(15)(16)(17). Clinical studies have reported beneficial effects of its administration in several diseases, but these improvements are of short duration.…”

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confidence: 99%

Homology Modeling and Site-directed Mutagenesis of Pyroglutamyl Peptidase II

Chávez‐Gutiérrez¹,

Matta‐Camacho²,

Osuna³

et al. 2006

Journal of Biological Chemistry

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“…Griffiths et al (15) reported that TRH was metabolized to inactivate TRH-OH by PEP in the cytosol, but not in the particulate fraction of brain. We also recently found that TRH-OH levels in the brain cytosolic fraction were decreased by JTP-4819 (data not shown).…”

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confidence: 99%

Effect of a Novel Prolyl Endopeptidase Inhibitor, JTP-4819, on Thyrotropin-Releasing Hormone-Like Immunoreactivity in the Cerebral Cortex and Hippocampus of Aged Rats

Shinoda

Okamiya

Toide

1995

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the effects of a novel prolyl endopeptidase inhibitor, JTP-4819on thyrotropinreleasing hormone (TRH)-like immunoreactivity (TRH-LI) in the cerebral cortex and hippocampus of aged rats. The TRH-LI content of both brain regions in aged rats was significantly lower than that in young rats. A single oral dose of JTP-4819 (3 mg/kg) restored the cortical TRH-LI content in aged rats, while doses of 0.3 -3 mg/kg restored it in the hippocampus. Repeated oral administration of JTP-4819 at a dose of 1 mg/kg for 21 days produced a significant increase of TRH-LI in the cerebral cortex, while it did so in the hippocampus at doses of 0.3 and 1 mg/kg. Our findings suggest that JTP-4819 may improve the functioning of TRHergic neurons, which deteriorate with senescence.

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Thyrotrophin-releasing hormone inactivation by human postmortem brain

Cited by 28 publications

References 21 publications

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

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

Homology Modeling and Site-directed Mutagenesis of Pyroglutamyl Peptidase II

Effect of a Novel Prolyl Endopeptidase Inhibitor, JTP-4819, on Thyrotropin-Releasing Hormone-Like Immunoreactivity in the Cerebral Cortex and Hippocampus of Aged Rats

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