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.