S 17092-1, A New Post-Proline Cleaving Enzyme Inhibitor: Memory Enhancing Effects and Substance P Neuromodulatory Activity

Lestage, Pierre; Lebrun, Cécile; Iop, Fabrice; Hugot, Anne; Rogez, Nathalie; Grève, Philippe; Favale, Dominique; Gandon, Marie-Hélène; Raimbault, Odile; Lepagnol, J.

doi:10.1007/978-1-4615-5337-3_92

Cited by 8 publications

(19 citation statements)

References 15 publications

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“…During the first three days of the 7-day pre-treatment period, S 17092 did not improve any of the cognitive functions measured (data not shown). These data are consistent with previous reports that showed chronic oral administration of S 17092 to be more effective than acute administration in increasing striatal substance P-like immunoreactivity (Lestage et al 1998). In other studies, chronic administration of S 17092 inhibited brain post-proline cleaving enzyme activity by more than 50% and improved learning and memory performances in both young scopolamine-treated and aged mice (Lestage et al 1998).…”

Section: Discussionsupporting

confidence: 92%

“…These data are consistent with previous reports that showed chronic oral administration of S 17092 to be more effective than acute administration in increasing striatal substance P-like immunoreactivity (Lestage et al 1998). In other studies, chronic administration of S 17092 inhibited brain post-proline cleaving enzyme activity by more than 50% and improved learning and memory performances in both young scopolamine-treated and aged mice (Lestage et al 1998). Although this was not directly assessed in the current studies, these findings suggest that cognition enhancing properties of S 17092 may be related to enhanced neuropeptide activities in the brain.…”

supporting

confidence: 92%

“…It is well known that neuropeptides can modulate the activity of dopamine as well as other neurotransmitters such as acetylcholine. In particular, cholinergic neurotransmission is facilitated by substance P (Lestage et al 1998). Proline endopeptidase inhibitors may improve cognitive function in MPTP-treated monkeys by indirectly promoting functions of a variety of neurotransmitter systems and/or by direct neuropeptide effects in the basal ganglia and other subcortical and cortical regions.…”

Section: Discussionmentioning

confidence: 99%

“…Because monkeys occasionally would not perform all of the tests in one day, task performance was usually assessed over two consecutive days of administration of the test dose of S 17092. Based on existing literature (Lepagnol et al 1996;Lestage et al 1998), the drug doses used were 1.0, 3.0 and 10.0 mg/kg. Different doses were administered in quasi-random order.…”

Section: Drug Administrationmentioning

confidence: 99%

“…S 17092 is a highly potent, orally active, cell permeant inhibitor of proline endopeptidase in brain (Barelli et al 1999;Lepagnol et al 1996). S 17092 can at least partially reverse scopolamine-induced amnesia and age-associated spatial delayed alternation deficits in mice, as well as increase striatal substance P immunoreactivity (Lestage et al 1998). The present study aimed to assess the extent to which S 17092 might improve cognition in chronic low dose MPTP-treated monkeys, a model of early-stage parkinsonism previously shown to exhibit cognitive deficits similar to those detected in PD patients (Schneider and Kovelowski 1990;Schneider and Roeltgen 1993).…”

mentioning

confidence: 99%

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Effects of the Prolyl Endopeptidase Inhibitor S 17092 on Cognitive Deficits in Chronic Low Dose MPTP-Treated Monkeys

Schneider

2002

Neuropsychopharmacology

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A number of neuropeptides are affected in Parkinson's disease and the enzyme proline endopeptidase contributes to the degradation of many of these neuropeptides, some of which are linked to a variety of cognitive functions. In the present study, the effects of the highly potent proline endopeptidase inhibitor S 17092 on cognitive deficits in monkeys induced by chronic low dose 2,3, It is generally recognized that non-demented Parkinson's disease (PD) patients exhibit a number of neuropsychological deficits, some of which are present even at the earliest stages of the disease (Lees and Smith 1983;Levin et al. 1989;Owen et al. 1993). Many of these deficits are 'frontal-like' in nature and consist of problems in attentional set shifting (Owen et al. 1993), distractibility (Sharpe 1990) planning and 'executive functions ' (Morris et al. 1988) and spatial working memory ). Parkinson's disease patients also may have difficulty performing a delayed matching-to-sample shortterm visual recognition memory task, but their problems appear more related to attentional difficulties rather than to visual recognition memory problems . The neurochemical deficits underlying the cognitive disturbances in PD patients are not completely known. While most of the motor symptoms of PD can be related to a nigrostriatal dopaminergic defect, the relationship between the dopaminergic defect and cognitive deficits in PD is less clear. Some cognitive deficits in PD may be dopa-responsive but others are not (Cooper et al. 1992;Lange et al. 1992). Some cognitive problems in PD patients are even exacerbated by dopaminergic therapy (Gotham et al. 1988). These findings suggest that the cognitive deficits in PD patients most likely arise from dysfunction of several cortical and subcortical neurotransmitter systems and functional circuits that cannot be normalized by dopamine replacement therapy alone. This is supported by the recent finding that a sub-type specific neuronal nicotinic acetylcholine receptor agonist, but not levodopa, was able to improve cognitive functioning in dopamine lesioned monkeys (Schneider et al. 1999). The nicotinic receptor agonist effects on cognition were most likely related to the ability of this compound to release dopamine from striatal, limbic and frontal cortical sites, norepinephrine from hippocampal, thalamic and frontal cortical sites and acetylcholine from various cortical and subcortical sites (Menzaghi et al. 1996;Sacaan et al. 1997).In addition to deficits in levels of various neurotransmitters in PD and in animal models of PD, decreased levels of various neuropeptides may also contribute to parkinsonian symptomatology (Mauborgne et al. 1983). Several neuropeptides, particularly substance P, have been implicated in learning and memory (Huston and Hasenohrl 1995) and are present endogenously in cortex and striatum. Substance P levels are also depleted in the striatum of monkeys made parkinsonian by exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since proline-containing neuropep...

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Section: Discussionsupporting

confidence: 92%

supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Drug Administrationmentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of the Prolyl Endopeptidase Inhibitor S 17092 on Cognitive Deficits in Chronic Low Dose MPTP-Treated Monkeys

Schneider

2002

Neuropsychopharmacology

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Prolyl endopeptidases

Gass

Khosla

2006

Cell. Mol. Life Sci.

120

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This review describes the structure and function of prolyl endopeptidase (PEP) enzymes and how they are being evaluated as drug targets and therapeutic agents. The most well studied PEP family has a two-domain structure whose unique seven-blade beta-propeller domain works with the catalytic domain to hydrolyze the peptide bond on the carboxyl side of internal proline residues of an oligopeptide substrate. Structural and functional studies on this protease family have elucidated the mechanism for peptide entry between the two domains. Other structurally unrelated PEPs have been identified, but have not been studied in detail. Human PEP has been evaluated as a pharmacological target for neurological diseases due to its high brain concentration and ability to cleave neuropeptides in vitro. Recently, microbial PEPs have been studied as potential therapeutics for celiac sprue, an inflammatory disease of the small intestine triggered by proline-rich gluten.

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Catabolism of the octadecaneuropeptide ODN by prolyl endopeptidase: Identification of an unusual cleavage site

et al. 2006

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S 17092-1, A New Post-Proline Cleaving Enzyme Inhibitor: Memory Enhancing Effects and Substance P Neuromodulatory Activity

Cited by 8 publications

References 15 publications

Effects of the Prolyl Endopeptidase Inhibitor S 17092 on Cognitive Deficits in Chronic Low Dose MPTP-Treated Monkeys

Effects of the Prolyl Endopeptidase Inhibitor S 17092 on Cognitive Deficits in Chronic Low Dose MPTP-Treated Monkeys

Prolyl endopeptidases

Catabolism of the octadecaneuropeptide ODN by prolyl endopeptidase: Identification of an unusual cleavage site

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