TY - JOUR
TI - Pyroglutamyl peptidase II inhibition enhances the analeptic effect of thyrotropin-releasing hormone in the rat medial septum
AU - Lazcano, I.
AU - Uribe, R.M.
AU - Martińez-Chávez, E.
AU - Vargas, M.A.
AU - Matziari, M.
AU - Joseph-Bravo, P.
AU - Charli, J.-L.
JO - JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
PY - 2012
VL - 342
TODO - 1
SP - 222-231
PB - 
SN - 0022-3565
TODO - 10.1124/jpet.112.192278
TODO - 5 oxoprolyl peptidase;  messenger RNA;  peptide hydrolase inhibitor;  prolyl endopeptidase inhibitor;  protirelin;  protirelin receptor;  pyroglutamyl peptidase II;  pyroglutamylasparaginylproline 7 amido 4 methylcoumarin;  pyroglutamylaspartylprolinamide;  thyrotropin releasing hormone receptor 1;  unclassified drug, analeptic activity;  animal cell;  animal experiment;  animal tissue;  article;  controlled study;  diagonal band of Broca;  dose response;  drug activity;  drug effect;  drug mechanism;  drug potentiation;  enzyme activity;  enzyme inhibition;  enzyme localization;  gene;  gene expression profiling;  gene expression regulation;  gene location;  male;  nonhuman;  priority journal;  protein expression;  protein function;  pyroglutamyl peptidase II gene;  rat;  receptor gene;  righting reflex;  septum pellucidum;  thyrotropin releasing hormone receptor 1 gene;  tissue distribution;  Wistar rat, Aminopeptidases;  Animals;  Central Nervous System Stimulants;  Male;  Peptides;  Pyrrolidonecarboxylic Acid;  Rats;  Rats, Wistar;  Receptors, Thyrotropin-Releasing Hormone;  Reflex, Righting;  RNA, Messenger;  Septum of Brain;  Serine Endopeptidases;  Thyrotropin-Releasing Hormone
TODO - Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) has multiple, but transient, homeostatic functions in the brain. It is hydrolyzed in vitro by pyroglutamyl peptidase II (PPII), a narrow specificity ectoenzyme with a preferential localization in the brain, but evidence that PPII controls TRH communication in the brain in vivo is scarce. We therefore studied in male Wistar rats the distribution of PPII mRNA in the septum and the consequence of PPII inhibition on the analeptic effect of TRH injected into the medial septum. Twelve to 14% of cell profiles expressed PPII mRNA in the medial septum-diagonal band of Broca; in this region the specific activity of PPII was relatively high. Twenty to 35% of PPII mRNA-labeled profiles were positive for TRH-receptor 1 (TRH-R1) mRNA. The intramedial septum injection of TRH reduced, in a dose-dependent manner, the duration of ethanol-induced loss of righting reflex (LORR). Injection of the PPII inhibitor pGlu-Asn-Pro-7-amido-4-methylcoumarin into the medial septum enhanced the effect of TRH. The injection of a phosphinic TRH analog, a higher-affinity inhibitor of PPII, diminished the duration of LORR by itself. In contrast, the intraseptal injection of pGlu-Asp-Pro-NH 2, a peptide that did not inhibit PPII activity, or an inhibitor of prolyl oligopeptidase did not change the duration of LORR. We conclude that in the medial septum PPII activity may limit TRH action, presumably by reducing the concentration of TRH in the extracellular fluid around cells coexpressing PPII and TRH-R1. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.
ER -