title: Pyroglutamyl peptidase II inhibition enhances the analeptic effect of thyrotropin-releasing hormone in the rat medial septum.
abstract: Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH(2)) 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.
authors.affiliation: Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Ave. Universidad 2001, Chamilpa, Cuernavaca, Mor. 62210, México.
authors.forename: Ivan
authors.initials: I
authors.lastname: Lazcano
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Uribe
authors.forename: Erick
authors.initials: E
authors.lastname: Martínez-Chávez
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Vargas
authors.forename: Magdalini
authors.initials: M
authors.lastname: Matziari
authors.forename: Patricia
authors.initials: P
authors.lastname: Joseph-Bravo
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Charli
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D008297:Male; D010455:Peptides / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D057897:Reflex, Righting / Q000235:genetics; D020665:Septum of Brain / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000494:pharmacology; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*
chemical_list: D000697:Central Nervous System Stimulants; D010455:Peptides; D012333:RNA, Messenger; D018025:Receptors, Thyrotropin-Releasing Hormone; C535055:TRH-receptor-1, rat; D013973:Thyrotropin-Releasing Hormone; D000626:Aminopeptidases; C023166:pyroglutamyl-peptidase II; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; D011761:Pyrrolidonecarboxylic Acid