Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on spatial memory and on cholinergic and peptidergic neurons in rats with ibotenate-induced lesions of the nucleus basalis magnocellularis

Shinoda, Masahiko; Miyazaki, Akira; Toide, Katsuo

doi:10.1016/s0166-4328(98)00005-9

Cited by 26 publications

(19 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, it has been shown that caspase-6 and prolyloligopeptidase participate in the processing of amyloid precursor protein (13,16,17). In addition, inhibitors of prolyloligopeptidase have been reported to enhance cognition and are being explored for the treatment of Alzheimer's disease (18,19). The Bcl-2 associated protein Bax was also down-regulated after training, again indicating a possible antiapoptotic effect of enrichment training (20).…”

Section: Resultsmentioning

confidence: 98%

Effects of environmental enrichment on gene expression in the brain

Rampon

Jiang

Dong

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

553

359

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 98%

Effects of environmental enrichment on gene expression in the brain

Rampon

Jiang

Dong

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

553

359

View full text Add to dashboard Cite

“…PO activity is required during normal brain function as its inhibitors enhance memory. [85][86][87][88] Changes in PO activity have previously been associated with mood disorders as well as a small number of other mental illnesses. 89,90 A recent report found that euthymic bipolar patients treated with Li þ had reduced plasma prolyl oligopeptidase activity.…”

Section: Preclinical and Clinical Studiesmentioning

confidence: 99%

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

2004

View full text Add to dashboard Cite

Inositol, a simple six-carbon sugar, forms the basis of a number of important intracellular signaling molecules. Over the last 35 years, a series of biochemical and cell biological experiments have shown that lithium (Li þ ) reduces the cellular concentration of myo-inositol and as a consequence attenuates signaling within the cell. Based on these observations, inositol-depletion was proposed as a therapeutic mechanism in the treatment of bipolar mood disorder. Recent results have added significant new dimensions to the original hypothesis. However, despite a number of clinical studies, this hypothesis still remains to be either proven or refuted. In this review of our current knowledge, I will consider where the inositol-depletion hypothesis stands today and how it may be further investigated in the future.

show abstract

“…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.…”

mentioning

confidence: 96%

“…The latter compound has improved an impaired performance after scopolamine treatment in passive avoidance task in rats and spatial discrimination task in mice [10]. JTP-4819 has improved performance of hippocampal-lesioned rats in a radial arm maze [11] and ibotenate-lesioned rats [7] and old rats [12] in Morris water maze. S 17092 has been safely administered to patients in clinical trials and has been reported to improve some aspects of ability [10].…”

mentioning

confidence: 99%

“…Since then, many POP inhibitors have been synthesized or extracted from microbes and medical plants, and their antiamnesic effects have been widely studied, usually in young adult rats [7,8,10,11,[14][15][16][17]. More recently, several hundred POP inhibitors have been synthesized in the University of Kuopio, and several of them, including KYP-2047, are under active investigation.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Jalkanen¹,

Puttonen²,

Venäläinen³

et al. 2006

Basic Clin Pharma Tox

View full text Add to dashboard Cite

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...

show abstract

Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on spatial memory and on cholinergic and peptidergic neurons in rats with ibotenate-induced lesions of the nucleus basalis magnocellularis

Cited by 26 publications

References 45 publications

Effects of environmental enrichment on gene expression in the brain

Effects of environmental enrichment on gene expression in the brain

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

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

Contact Info

Product

Resources

About