Effect of prolyl endopeptidase inhibition on arginine-vasopressin and thyrotrophin-releasing hormone catabolism in the rat brain.
Compound S 17092 is a potent and selective inhibitor of prolyl endopeptidase (EC 3.4.21.26, PEP) that may be of therapeutic value for the treatment of memory impairment associated with neurodegenerative diseases. In the present study, we investigated the effects of S 17092 on the catabolism of the promnesic neuropeptides thyrotrophin-releasing hormone (TRH) and arginine-vasopressin (AVP) in the rat brain. In vitro, bacterial PEP hydrolysed both TRH and AVP, and the breakdown of the two peptides was almost completely prevented by 10(-5) M S 17092. In vivo, a single oral administration of S 17092 provoked a significant increase in TRH-like immunoreactivity (TRH-LI) in the cerebral cortex (+63% for a 10 mg/kg dose and +72% for a 30 mg/kg dose), as well as AVP-LI in the hippocampus (+54% for a 30 mg/kg dose), but did not affect TRH-LI in the amygdala nor AVP-LI in the cerebral cortex. Chronic administration of S 17092 (10 or 30 mg/kg daily) lead to a significant increase in THR-LI in the cerebral cortex (+55% and +56%, respectively), but did not modify AVP-LI in the hippocampus, nor in the cerebral cortex. These results show that the selective PEP inhibitor S 17092 increases TRH and AVP content in discrete regions of the rat brain. The present data suggest that the promnesic and antiamnesic effects of S 17092 can be accounted for, at least in part, by blockage of AVP and TRH degradation by PEP.
Bellemère
G
G
INSERM U413, European Institute for Peptide Research, Laboratory of Cellular and Molecular Neuroendocrinology, UA CNRS, University of Rouen, Mont-Saint-Aignan, France.
Vaudry
H
H
Morain
P
P
Jégou
S
S
D000679:Amygdala / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D018697:Nootropic Agents / Q000008:administration & dosage; D011480:Protease Inhibitors / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage*; D053778:Thiazolidines; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism*
D007211:Indoles; D018697:Nootropic Agents; D011480:Protease Inhibitors; C118986:S 17092-1; D013844:Thiazoles; D053778:Thiazolidines; D001127:Arginine Vasopressin; D013973:Thyrotropin-Releasing Hormone; D012697:Serine Endopeptidases