Benzyloxycarbonyl-Methionyl-2(S)-Cyanopyrrolidine, a Prolyl Endopeptidase Inhibitor, Modulates Depression-Like Behavior of Rats in Forced Swimming Test and Activities of Proline-Specific Peptidases in the Brain Structures

Krupina, N. A.; Bogdanova, N. G.; Хлебникова, Н. Н.; Zolotov, N. N.; Крыжановский, Г. Н.

doi:10.1007/s10517-013-2010-y

Cited by 8 publications

(6 citation statements)

References 11 publications

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“…DPP-IV-deficient rats demonstrated anxiolytic-like behavior and reduced stress-like responses [24]. In our studies, we have revealed increased activities of both DPP-IV and PEP in several brain structures in rat models of stress-induced depression-like state and experimental depressive-like syndrome associated with a dopamine deficit induced by the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [25] [26].…”

Section: Introductionmentioning

confidence: 53%

Neonatal Exposure to the Dipeptidyl Peptidase-IV Inhibitors Diprotin A and Sitagliptin Induces Depression-Like Behavior, Anxiety, and Latent Aggression in Adolescent and Adult Rats

Krupina¹,

Хлебникова²

2016

JBBS

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Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) is involved in the pathophysiology of psycho-emotional disorders. Recently, we have shown that adolescent and adult rats exhibit an increase in anxiety and depression-related behaviors after neonatal administration of a synthetic non-competitive inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine. In the present study, we tested the effects of two competitive, selective DPP-IV inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg), administered at postnatal days 5 -18 on the emotional and motivational behavior of adolescent and adult rats. We observed increased anxiety in one-month-old diprotin A-or sitagliptin-treated rats in the elevated plus maze; diprotin A also enhanced the animals' anxiety score using a ranked scale for evaluating anxiety and phobias. In the sucrose consumption and preference test, depressive-like behavior was pronounced in both the diprotin A-and sitagliptin-treated one-month-old animals, while only the diprotin A-treated rats exhibited a decrease in sucrose consumption at the age of 2 months. The diprotin A-treated rats also demonstrated behavioral despair and decreased activity in the forced swimming test within 1 -3 months of age. Increased aggression was observed in 1 -3-month-old diprotin A-treated rats and in two-month-old sitagliptin-treated rats. These findings support the hypothesis that DPP-IV is involved in the genesis of emotional and motivational disorders. Additionally, the results show that diprotin А impairs the adolescent and adult rats' behavior more significantly than sitagliptin when the animals were treated with the DPP-IV

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Section: Introductionmentioning

confidence: 53%

Neonatal Exposure to the Dipeptidyl Peptidase-IV Inhibitors Diprotin A and Sitagliptin Induces Depression-Like Behavior, Anxiety, and Latent Aggression in Adolescent and Adult Rats

Krupina¹,

Хлебникова²

2016

JBBS

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“…In the models of stress-induced depression in rats in the forced swimming test and anxiety-depressive state induced by administration of DPP-IV inhibitor in the early postnatal period, the antidepressant effect of Z-Met-Prd-N was followed by normalization of PEP and DPP-IV activities in brain structures [1,9]. Analysis of changes in prolyl-specifi c endopeptidase activity and effi ciency of PEP inhibitors in various models of affective disorders during different administration regimens drove us to a conclusion that antidepressant activity is a common property of PEP inhibitors with various mechanisms, which opens prospects for creation of a group of antidepressants based on PEP inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…In our experiments, the injections of methionyl-2(S)-cyanopyrrolidine, a synthetic DPP-IV inhibitor, to rats during the early postnatal period were found to induce the development of anxious-depressive syndrome in adolescent and adult rats [3]. It has been demonstrated on various models of affective disorders that activity of PEP and DPP-IV increases in rat brain structures involved in emotion and motivation behavior [1,2,6].…”

mentioning

confidence: 99%

“…Subchronic injections of Z-Met-Prd-N under these conditions alleviated clinical symptoms of depression on the rat model of anxious-depressive syndrome induced by postnatal treatment with a DPP-IV inhibitor [3]. Acute administration of Z-Met-Prd-N reduces the manifestations of despair behavior on the model of stress-induced depressive state in the forced swimming test [1]. Previous experiments on the rat model of MPTP-induced depressive syndrome has showed that subchronic administration of a competitive inhibitor for PEP benzyloxycarbonyl-alanyl-proline (Z-Ala-Pro-OH, during the 2nd week of pre-neurotoxin administration, 30 min before MPTP injection) does not signifi cantly affect clinical presentations for the syndrome, but promoted elimination of depressive symptoms in rat behavior after MPTP withdrawal [8].…”

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confidence: 99%

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Effect of Prolyl Endopeptidase Inhibitor Benzyloxycarbonyl-Methionyl-2(S)-Cyanopyrrolidine on the Course of Experimental Depressive Syndrome in Rats

et al. 2013

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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.

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“…In addition, POP located in activated microglia is a potential target for neuroprotection ( Natunen et al, 2019 ). Indeed, previous studies have shown that low molecular weight inhibitors of POP had pronounced neuroprotective, nootropic, antidepressant, and anxiolytic properties ( Penttinen et al, 2011 ; Krupina et al, 2013a ). Indeed, three POP inhibitors (JTP-4819, Z-321, and S 17092) are in phase I and/or II clinical trials, thus demonstrating that small molecule POP inhibitors could be safely administered in humans ( Svarcbahs et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Effect of Novel Cyanopyrrolidine-Based Prolyl Oligopeptidase Inhibitors in Rat Models of Amnesia

et al. 2021

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Prolyl oligopeptidase (POP) is a large cytosolic serine peptidase that is altered in patients with Alzheimer’s disease, Parkinsonian syndrome, muscular dystrophies, and other denervating diseases. Thus, POP may represent a relevant therapeutic target for treatment of neuropsychiatric disorders and neurodegenerative diseases. Here, we report the characterization of five novel cyanopyrrolidine-based compounds (BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, CbzGlnPrdN, and CbzAlaPrdN) and show that they are potent inhibitors of POP and are predicted to penetrate the blood-brain barrier (BBB). Indeed, we show that CbzMetPrdN penetrates the rat BBB and effectively inhibits POP in the brain when administered intraperitoneally. Furthermore, molecular modeling confirmed these compounds likely inhibit POP via interaction with the POP catalytic site. We evaluated protective effects of the cyanopyrrolidine-based POP inhibitors using scopolamine- and maximal electroshock-induced models of amnesia in rats and showed that BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, and CbzGlnPrdN significantly prolonged conditioned passive avoidance reflex (CPAR) retention time when administered intraperitoneally (1 and 2 mg/kg) before evaluation in both models of amnesia, although CbzAlaPrdN was not effective in scopolamine-induced amnesia. Our data support previous reports on the antiamnesic effects of prolinal-based POP inhibitors and indicate an important role of POP in the regulation of learning and memory processes in the CNS.

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Benzyloxycarbonyl-Methionyl-2(S)-Cyanopyrrolidine, a Prolyl Endopeptidase Inhibitor, Modulates Depression-Like Behavior of Rats in Forced Swimming Test and Activities of Proline-Specific Peptidases in the Brain Structures

Cited by 8 publications

References 11 publications

Neonatal Exposure to the Dipeptidyl Peptidase-IV Inhibitors Diprotin A and Sitagliptin Induces Depression-Like Behavior, Anxiety, and Latent Aggression in Adolescent and Adult Rats

Neonatal Exposure to the Dipeptidyl Peptidase-IV Inhibitors Diprotin A and Sitagliptin Induces Depression-Like Behavior, Anxiety, and Latent Aggression in Adolescent and Adult Rats

Effect of Prolyl Endopeptidase Inhibitor Benzyloxycarbonyl-Methionyl-2(S)-Cyanopyrrolidine on the Course of Experimental Depressive Syndrome in Rats

Therapeutic Effect of Novel Cyanopyrrolidine-Based Prolyl Oligopeptidase Inhibitors in Rat Models of Amnesia

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