Beneficial Effect of Prolyl Oligopeptidase Inhibition on Spatial Memory in Young but Not in Old Scopolamine‐Treated Rats

Abstract

The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP-2047 on spatial memory of young (3-monthold) and old (8-to 9-month-old) scopolamine-treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats. In addition, inositol-1,4,5-trisphosphate (IP 3 ) levels were assayed in rat cortex and hippocampus after effective 2.5-day POP inhibition. KYP-2047 (1 or 5 mg/kg 30 min. before daily testing) dose-dependently improved the escape performance (i.e. latency to find the hidden platform and swimming path length) of the young but not the old rats in the water maze. POP inhibition had no consistent effect on substance P levels in cortex, hippocampus or hypothalamus, and only a modest increase in neurotensin concentration was observed in the hypothalamus after a single dose of KYP-2047. Moreover, IP 3 concentrations remained unaffected in cortex and hippocampus after POP inhibition. In conclusion, the behavioural data support the earlier findings of the promnesic action of POP inhibitors, but the mechanism of the memory-enhancing action remains unclear.In addition to the cholinergic neurones, many neuropeptides may play a role in cognitive functions such as learning and memory. These peptides include vasopressin, neurotensin, oxytocin, substance P and bradykinin [1,2]. A common feature of the above-mentioned promnesic neuropeptides is their sensitivity to prolyl oligopeptidase (POP, EC 3.4.21.26), also known as prolyl endopeptidase [1]. POP is a member of the serine protease family that hydrolyses peptide bonds at the carboxy terminal of  -proline. The effects of POP in memory disorders are somewhat conflicting. On one hand, some findings suggest that a decrease in POP activity is characteristic of a generalized process of neurodegeneration, including Alzheimer's disease and dementia [3]. However, for example in Alzheimer's disease, the changes in POP activities depend on which brain areas are being investigated. In cerebral cortex, a reduction in POP activity has been observed, whereas in occipital cortex, the POP activity seems to increase [4]. It has been proposed but not proved that these alterations in POP activity in Alzheimer's disease and dementia account for some of the observed changes in neuropeptide levels. In Alzheimer's disease, vasopressin and substance P levels decrease in cortical areas and hippocampus [5], areas implicated in cognitive processes. Furthermore, increased levels of neuropeptides have been shown to improve cognitive function in experimental animals [6,7].These observations would seem to indicate that manipulations of POP activity and its secondary effects on neuropeptide levels could represent a potential therapeutic target for treatment of cognitive disorders. Several POP inhibitors have been studied in animals. Studies with rats have demonstrated memo...

Low molecular weight inhibitors of Prolyl Oligopeptidase: a review of compounds patented from 2003 to 2010

“…Nevertheless, later studies demonstrated the high complexity of this mechanism in memory functions. The low reproducible results, poor dosedependency and non-predictable behavior of POP inhibition were incoherent with a simple direct effect [30,47,48]. The effects of POP inhibition were also tested in the treatment of cognitive deficits related to neurodegenerative processes.…”

“…With few exceptions of in vivo animal [85,86] and human [53,54,58] pharmacodynamic studies, the lack of data concerning toxicology, blood-brain barrier permeability and mainly human pharmacokinetic and pharmacodynamic studies hinders any assessment. Moreover, a plethora of animal models has been used to evaluate the in vivo effects of inhibitors [27,46,44,[47][48][49][50][51][52]; however, it seems that the control parameters are not properly defined. Hence, choosing the optimal cognition-enhancing test model may be one of the key points in the future.…”

Encouraging effect of Brahmi Ghrita in amnesia

“…Scopolamine, acetylcholine receptor antagonist, is reported to impair cognitive performances [21] especially spatial learning and memory. [22] It exerts amnesic effect equally in various behavioural models of memory including Morris water maze, [23] etc., and considered as a reliable tool to study anti-amnesic effects. It is muscarinic cholinergic antagonist, and capable of inducing transient memory impairment in normal subjects [24] due to this rats treated with scopolamine showed an increase in transfer latency on elevated maze plus, increase step through latency in passive avoidance and increased total trial, shock trial and total time in active avoidance test indicate that scopolamine produces amnesia in animals that is it acts as anti-amnestic agent.…”

Simultaneous 19F NMR Screening of Prolyl Oligopeptidase and Dipeptidyl Peptidase IV Inhibitors

“…[9] Clinical studies have also shown that blood plasma levels of POP activity are increased in patients with bipolar affective disorder (BD). [11] Furthermore, POP inhibition reverses scopolamine-induced amnesia in rats [12] and improves cognition in MTPT (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated primates [13] and aged rats. [14] Although the mechanism by which POP regulates IP 3 levels remains to be clarified, the mentioned data strongly suggest that the development of selective POP inhibitors would be beneficial in the treatment of patients with cognitive disorders.…”