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

Abstract

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.

Ontogeny of Soluble and Particulate Prolyl Endopeptidase Activity in Several Areas of the Rat Brain and in the Pituitary Gland

“…The levels of certain proline-containing peptides, such as substance P and TRH, have been reported to be decreased in the brain cortex and hippocampus of aged rats [Shinoda et al, 1995;Toide et al, 1997a, b]. Our study revealed decreases in the levels of activity of soluble PEP in the CNS during senescence.…”

“…This increased particulate PEP activity could be involved in the decreased levels of certain peptides such as AVP, TRH and substance P in old animals. These peptides are involved in senescence and have been suggested to be trophic factors for lower motor neurons [Shinoda et al, 1995;Toide et al, 1995b;Van den Bergh et al, 1996].…”

“…Among them, PEP has been shown to be functionally involved in the aging process and in neurodegenerative disorders such as Alzheimer's disease [Ichai et al, 1994;Ishiura et al, 1990]. In this sense, long-term inhibition of PEP, which suppresses amyloid formation in senescence-accelerated mice [Fukunari et al, 1994;Kato et al, 1997], appears to improve the functionality of THRergic neurons, which deteriorate with senescence [Shinoda et al, 1995;Shishido et al, 1999] and to increase substance P and argininevasopressin-like immunoreactivity in the brain of aged rats [Toide et al, 1995b].…”

Localization of the mRNA encoding prolyl endopeptidase in the rat brain and pituitary

“…Previous in vivo studies have shown that administration of selective PEP inhibitors provokes a significant increase in the cerebral concentration of SP (Toide et al, 1996;Bellemère et al, 2003), ␣-MSH (Bellemère et al, 2003), AVP (Miura et al, 1995;Toide et al, 1996), and TRH (Shinoda et al, 1995;Toide et al, 1996). To determine whether PEP may be actually involved in the metabolism of these neuropeptides, the localization of PEPexpressing cells has been compared with the distribution of the mRNAs encoding the SP receptors NK1 and NK3, the ␣-MSH receptors MC3 and MC4, the AVP receptors V1a and V1b, and the TRH receptors TRH-R1 and TRH-R2 (Table 1).…”

Parasite Prolyl Oligopeptidases and the Challenge of Designing Chemotherapeuticals for Chagas Disease, Leishmaniasis and African Trypanosomiasis

“…This feature has motivated several research groups to explore the physiological roles of human POP family members and the therapeutic potential of their inhibitors to treat neurological, hormonal and metabolic disorders such as Alzheimer's disease, depression, abnormal blood pressure and type II diabetes. Two DPPIV inhibitors, vildagliptin and sitagliptin, are already in clinical use [8][9][10][11][12]. Due to their ability to cleave peptide bonds on the carboxyl end of proline residues, POP has also been studied as a potential therapeutic component for the treatment of celiac disease, a chronic enteropathy induced by immunotoxic and proline-rich gluten peptides [13].…”