A novel prolyl endopeptidase inhibitor, JTP-4819, with potential for treating Alzheimer's disease.
The pharmacological actions of JTP-4819, a new prolyl endopeptidase (PEP) inhibitor targeted for the treatment of Alzheimer's disease, are reviewed with respect to its effects on PEP activity, brain neurotransmitters, and memory-related behaviour in rats. JTP-4819 was shown to be a very potent and specific inhibitor of PEP. At nanomolar concentration, JTP-4819 inhibited the degradation of substance P, arginine-vasopressin, and thyrotropin-releasing hormone by PEP in supernatants of the rat cerebral cortex and hippocampus. Repeated administration of JTP-4819 reversed the aging-induced decrease in brain substance P-like and thyrotropin-releasing hormone-like immunoreactivity, suggesting that this drug may be able to improve the imbalance of peptidergic neuronal systems that develops with senescense by inhibiting PEP activity. JTP-4819 increased acetylcholine release from the frontal cortex and hippocampus, regions closely associated with memory, in both young and aged rats. In addition, it improved performance in several memory and learning-related tests (e.g., the Morris water maze task in aged or MCA-occluded rats and the passive avoidance test). This memory-enhancing effect of JTP-4819 may result from prevention of the metabolic degradation of brain neuropeptides by PEP as well as from the enhancement of acetylcholine release. Taken together, these unique and potent pharmacological actions of JTP-4819 suggest that it may have the potential to be used for treating Alzheimer's disease.
Toide
K
K
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
Shinoda
M
M
Iwamoto
Y
Y
Fujiwara
T
T
Okamiya
K
K
Uemura
A
A
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D018782:Maze Learning / Q000187:drug effects; D017551:Microdialysis; D009479:Neuropeptides / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology*; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism*
D009479:Neuropeptides; D018697:Nootropic Agents; D011480:Protease Inhibitors; D011759:Pyrrolidines; C094211:JTP 4819; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases