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

Abstract

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...

Radical scavenging, prolyl endopeptidase inhibitory, and antimicrobial potential of a cultured Himalayan lichenCetrelia olivetorum

“…Various authors have reported an unusually higher PEP levels in the patients suffering from AD and suggested that PEP might be one of the several factors involved in cognitive decline associated with aging (Lee & Paik, 2003;Tezuka et al, 1999). Therefore, PEP inhibition might have a therapeutic value in the treatment of AD and PEP inhibitors could be a novel anti-amnesic drug Schneider et al, 2002;Toide et al, 1997).…”

Peptidomics of the Prolyl Peptidases

“…The identification of these substrates led to new hypotheses about Prep function, which were tested in vivo using pharmacological Prep inhibitors. Interestingly, several of these experiments suggested that Prep inhibition would lead to improved cognitive function in mammals, which was later verified (15)(16)(17)(18). However, the underlying mechanism for this improvement is still under investigation because some of the Prep substrates predicted to be responsible for this effect were unaffected, or only modestly affected, upon Prep inhibition (19)(20)(21).…”

“…The unique biochemical activity of Prep, namely the ability to cleave peptides at proline amino acids, has prompted a great deal of research into the biochemical, cellular, and physiological functions of this protein (9). In vitro assays have identified Prep substrates that range from the tripeptide, thyrotropin-releasing hormone, to a 31 amino acid peptide, beta endorphin (9,34), which led to new hypotheses about the physiological role of Prep, including a role in cognitive function (15)(16)(17)(18).…”

Memory-improving Effects of Fermented Sea Tangle Saccharina japonica in Normal Mice

“…AChE nausea, vomiting, bradycardia, anorexia sweating (Mehta et al, 2012 (Mannisto et al, 2007;Schneider et al, 2002;. PEP target .…”