Age-induced increase of leucine enkephalin enzyme degradation in human plasma

Babst, Reto; Bongiorno, Lucilla; Marini, Mario; Marzano, Marina; Spagnoli, Giulio C.; Roda, L.Giorgio; Urbani, Alessandra

doi:10.1016/s0196-9781(98)00061-8

Cited by 7 publications

(4 citation statements)

References 36 publications

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“…Protocol included healthy, drugfree volunteers, and drug-free inpatient chronic schizophrenics, chronic users of various drugs of addiction, including or excluding alcohol, chronic alcoholics and migraineurs. Furthermore, interindividual variation for these kinetic parameters were similar among the populations studied, reflecting what would be expected from 'normal' individual differences and experimental variance (pilot data on age [29,30] indicates the need for further studies; same participating subjects in both reports). Similarly, the identity and/or relative ratio of the reaction products formed remained essentially unchanged despite variations in plasma storage times or repeated sample freezing and thawing [13].…”

Section: Discussionmentioning

confidence: 60%

In vitro Human Plasma Leucine<sup>5</sup>-Enkephalin Degradation Is Inhibited by a Select Number of Drugs with the Phenothiazine Molecule in Their Chemical Structure

Mosnaim¹,

Puente²,

Saavedra³

et al. 2002

Pharmacology

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A number of drugs with the phenothiazine molecule in their chemical structure inhibit in a dose-dependent manner human plasmatic aminopeptidase leucine⁵-enkephalin (LEU) metabolism. Half-life peptide degradation was significantly increased by thioridazine > fluphenazine > As-1397 [10-(α-diethylaminopropionyl)phenothiazine] ≧ promethazine ≧ chlorpromazine (final drug conc. 10^–4M); t1/2 (± SD) 21.2 ± 1.1, 19.6 ± 1.0, 17.2 ± 0.9, 17.1 ± 1.0, and 17.1 ± 1.1 min, respectively. Control and bacitracin (known aminopeptidase inhibitor) values were 11.8 ± 1.0 and 31.3 ± 1.7 min, respectively. These drugs significantly decreased (listed in the same order) LEU degradation initial velocity; Iv (± SD) 0.77 ± 0.2, 0.82 ± 0.2, 0.92 ± 0.3, 0.93 ± 0.2, 0.94 ± 0.3 pg LEU/min, respectively. Control and bacitracin 1.10 ± 0.3 and 0.20 ± 0.1 pg LEU/min, respectively. Values represent results from 5 samples, each obtained by pooling 6 individual plasmas (4 male and 2 female; n = 30 healthy, drug-free volunteers). However, neither the phenothiazines ethopropazine, methotrimeprazine, prochlorperazine and trifluoperazine nor the various commonly used heterocyclic antipsychotics tested, e.g., molindone, loxapine, clozapine, haloperidol, sulpiride and thiothixene inhibited plasma LEU degradation kinetics. Our results failed to show correlations between chemical structure, antipsychotic properties and ability to inhibit plasmatic aminopeptidase LEU degradation. Whereas, presence of the phenothiazine molecule appears to be necessary for enzyme inhibition, only five out of nine substituted phenothiazines tested exhibited this effect. Furthermore, there was a lack of correlation between phenothiazines antipsychotic properties and their capacity to inhibit aminopeptidase activity, a property shown by promethazine (antihistaminic) and As-1397 (selective butyrylcholinesterase inhibitor) but lacking in prochlorperazine and trifluoperazine. Our results provide information which could lead to the rational design of agents capable to modulate the bioavailability of enkephalin and other endogenous aminopeptidase-degraded peptides believed to be involved in the etiology and/or pathophysiology associated with various disease conditions. Whether their development could find useful pharmacological applications remains to be explored.

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Section: Discussionmentioning

confidence: 60%

In vitro Human Plasma Leucine<sup>5</sup>-Enkephalin Degradation Is Inhibited by a Select Number of Drugs with the Phenothiazine Molecule in Their Chemical Structure

Mosnaim¹,

Puente²,

Saavedra³

et al. 2002

Pharmacology

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“…We also examined a subset of animals at 22 days postendometriosis induction, and similar to the current results, no changes in opioid peptides within the PAG were observed (unpublished results). In vivo hydrolysis of leu-enkephalin has been reported to be decreased by 4 weeks after trauma 58 ; thus, changes in opioid peptides after endometriosis are probably short-lived and are likely associated with time points closer to the onset. However, even small alterations in the receptors expression, as observed here, can lead to changes in structure activity and output signaling, regardless of equal production in opioid peptides.…”

Section: Cross Talk Between Mor and Nmda Functional Implicationsmentioning

confidence: 99%

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

et al. 2016

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Studies have examined how endometriosis interacts with the nervous system, but little attention has been paid to opioidergic systems, which are relevant to pain signaling. We used the autotransplantation rat model of endometriosis and allowed to progress for 60 days. The brain was collected and examined for changes in endogenous opioid peptides, mu opioid receptors (MORs), and the N-methyl-D-aspartate subunit receptor (NR1) in the periaqueductal gray (PAG), since both of these receptors can regulate PAG activity. No changes in endogenous opioid peptides in met-and leu-enkephalin or b-endorphin levels were observed within the PAG. However, MOR immunoreactivity was significantly decreased in the ventral PAG in the endometriosis group. Endometriosis reduced by 20% the number of neuronal profiles expressing MOR and reduced by 40% the NR1 profiles. Our results suggest that endometriosis is associated with subtle variations in opioidergic and glutamatergic activity within the PAG, which may have implications for pain processing.

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“…Unfortunately, their use as drugs is hampered by their short half-life in biological fluids. Additionally, degradation of these peptides increases in the microenvironment of the inflamed tissue, due to the elevated temperature, acidosis, and enhanced proteolytic activity of some enzymes 15–17 . Administration of more stable opioid peptide analogs produces significant peripherally-mediated analgesia in human 18–21 and animal models 22–25 .…”

Section: Introductionmentioning

confidence: 99%

Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF₃-Phe-Asp]NH₂

Piekielna-Ciesielska

Mollica

Pieretti

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Opioid peptides and opiate drugs such as morphine, mediate their analgesic effects, but also undesired side effects, mostly through activation of the mu opioid receptor. However, delta- and kappa-opioid receptors can also contribute to the analgesic effects of opioids. Recent findings showed that simultaneous activation of multiple opioid receptors may result in additional analgesia with fewer side effects. Here, we evaluated the pharmacological profile of our formerly developed mixed mu/kappa-opioid receptor ligands, Dmt-c[D-Lys-Phe-Phe-Asp]NH2 (C-36) and Dmt-c[D-Lys-Phe-p-CF3-Phe-Asp]NH2 (F-81). The ability of these peptides to cross the blood–brain barrier was tested in the parallel artificial membrane permeability (PAMPA) assay. On the basis of the hot-plate test in mice after central and peripheral administration, analog F-81 was selected for the anti-nociceptive and anti-inflammatory activity assessment after peripheral administration.

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Age-induced increase of leucine enkephalin enzyme degradation in human plasma

Cited by 7 publications

References 36 publications

In vitro Human Plasma Leucine<sup>5</sup>-Enkephalin Degradation Is Inhibited by a Select Number of Drugs with the Phenothiazine Molecule in Their Chemical Structure

In vitro Human Plasma Leucine<sup>5</sup>-Enkephalin Degradation Is Inhibited by a Select Number of Drugs with the Phenothiazine Molecule in Their Chemical Structure

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF₃-Phe-Asp]NH₂

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Age-induced increase of leucine enkephalin enzyme degradation in human plasma

Cited by 7 publications

References 36 publications

In vitro Human Plasma Leucine<sup>5</sup>-Enkephalin Degradation Is Inhibited by a Select Number of Drugs with the Phenothiazine Molecule in Their Chemical Structure

In vitro Human Plasma Leucine<sup>5</sup>-Enkephalin Degradation Is Inhibited by a Select Number of Drugs with the Phenothiazine Molecule in Their Chemical Structure

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF3-Phe-Asp]NH2

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Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF₃-Phe-Asp]NH₂