Behavioral Changes in Rats Induced by a Dipeptidyl Peptidase IV Inhibitor Methionyl-2(S)-Cyanopyrrolidine: Experimental Model of Anxiety-Depression Disorder

Abstract

Administration of a synthetic dipeptidyl peptidase IV inhibitor methionyl-2(S)-cyanopyrrolidine (1 mg/kg) to rats during the early postnatal period was followed by the development of behavioral changes in young and adult animals. The degree of anxiety in the elevated plus maze increased in treated rats at the age of 1-2 months. Depressive behavior in the forced swimming test was typical of animals aging 2-3 months. Diazepam reduced the severity of anxiety in treated rats. Melipramine had a normalizing effect on swimming behavior. A novel prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine had the antidepressant properties.

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

“…Previously, we have shown that postnatal methionyl-2(S)-cyano-pyrrolidine, a synthetic non-competitive irreversible inhibitor of DPP-IV, causes anxiety-and depression-related behaviors in adolescent and adult rats (from the first to the seventh month) [29] [47]. In the present study, we have demonstrated that rat pups exposed to DPP-IV inhibitors with different mechanisms of action in the early postnatal period might develop persistent behavioral disorders.…”

“…By comparing the appearance and maintenance of the behavioral disorders in the diprotin A-and sitagliptintreated, we concluded that, in this study, diprotin A caused more pronounced and long-term consequences, which are comparable to the effects of methionyl-2(S)-cyano-pyrrolidine [29]. The latter inhibitor was used at a dose of 1 mg per kg at the same time points with an approximately equimolar amount (MW 199.27).…”

“…Brust et al [28] showed an increase in the activity of the membrane-bound serine peptidase DPP-IV in brain homogenates of 1 -4-week-old Wistar rats. Based on these observations, we determined that rats exposed to a synthetic non-competitive irreversible inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine, for two weeks after birth on postnatal days 5 -18 demonstrated increased anxiety-and depression-related behaviors in adolescence and adulthood [29]. The behavioral alterations were associated with latent aggression [30] and with increased DPP-IV and PEP activity in some brain regions [31].…”

Changes in Gene Expression Profiles in Adult Rat Brain Structures after Neonatal Action of Dipeptidyl Peptidase-IV Inhibitors

“…In the present study, dpp4 gene expression was increased in the striatum in rats after neonatal exposure to sitagliptin, and prep gene expression was increased in the same structure in rats after neonatal exposure to diprotin A. The results of the study confirm the participation of the proline-specific peptidases DPP-IV and PREP in the pathogenesis of emotional and motivational disorders, as discussed in our previous work [27-29]. …”

“…In our studies, equimolar doses of the synthetic noncompetitive irreversible inhibitor of DPP-IV, methionyl-2(S)-cyanopyrrolidine, and selective competitive DPP-IV inhibitors, sitagliptin and tripeptide diprotin A, which is the DPP-IV substrate, administered in rats on PND 5–18 led to the development of an anxiety-depression-like state with increased aggression manifested in the social contact test, which was conducted after 2–3 days of isolation [27-29]. The data indicate that DPP-IV could participate in the genesis of emotional and motivational disorders, but it does not describe possible mechanisms for such participation.…”