benzyloxycarbonyl-methionyl-2(s)-cyanopyrrolidine and Depressive-Disorder

The effects of noncompetitive prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine were studied in rats with the experimental dopamine deficiency-dependent depressive syndrome induced by systemic injections of a pre-neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin for 14 days. The inhibitor (3.0 mg/kg, i.p., 30 min before pre-neurotoxin injection on days 8-14) alleviated depression symptoms and promoted normalization of behavioral activity after drug withdrawal. The obtained data reflected therapeutic antidepressant properties of inhibitor for prolyl endopeptidase benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anxiety; Behavior, Animal; Body Weight; Depressive Disorder; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Dopamine; Male; Methionine; Prolyl Oligopeptidases; Pyrrolidines; Rats; Rats, Wistar; Serine Endopeptidases; Sucrose

A noncompetitive synthetic inhibitor of prolyl endopeptidase benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine (1.0 mg/kg intraperitoneally for 2 weeks) prevented the increase in activity of prolyl endopeptidase in the frontal cortex, striatum, and hypothalamus and activation of dipeptidyl peptidase IV in the frontal cortex of rats with experimental dopamine deficiency-dependent depressive syndrome caused by administration of proneurotoxin MPTP (2 weeks). Our results suggest that the antidepressive effect of prolyl endopeptidase inhibitor is at least partly related to prevention of enzyme activation in the frontal cortex. The antistress effect of this substance can be associated with prevention of enzyme activation in the hypothalamus.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antidepressive Agents; Behavior, Animal; Corpus Striatum; Depressive Disorder; Dipeptidyl Peptidase 4; Drug Evaluation, Preclinical; Enzyme Activation; Frontal Lobe; Hypothalamus; Injections, Intraperitoneal; Male; Methionine; Prolyl Oligopeptidases; Protease Inhibitors; Pyrrolidines; Rats; Rats, Wistar; Serine Endopeptidases

Activities of prolyl endopeptidase and dipeptidyl peptidase IV in the frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocampus were measured in rats with the experimental anxious-depressive syndrome induced by treatment with a dipeptidyl peptidase IV inhibitor during the early postnatal period (days 5-18). Prolyl endopeptidase activity was elevated in the frontal cortex, hypothalamus, and nucleus accumbens. Increased activity of dipeptidyl peptidase IV was observed in the hypothalamus and striatum. Norepinephrine/serotonin reuptake inhibitor, imipramine, and noncompetitive prolyl endopeptidase inhibitor, benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, were shown to abolish depression-like behavior of animals in the forced swimming test. These compounds had a normalizing effect on activities of prolyl endopeptidase and dipeptidyl peptidase IV in brain structures of rats.

Topics: Animals; Animals, Newborn; Antidepressive Agents, Tricyclic; Anxiety; Brain; Depressive Disorder; Dipeptidyl Peptidase 4; Imipramine; Male; Methionine; Prolyl Oligopeptidases; Protease Inhibitors; Pyrrolidines; Rats; Rats, Wistar; Serine Endopeptidases; Swimming