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

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.

INFLUENCE OF ZINC ALIMENTARY TREATMENT ON NORMAL AND PATHOLOGICAL MOTOR BEHAVIOR OF RATS

Chronic experiments were performed on rats to study the influence of prolonged acetic zinc alimentary treatment on normal (spontaneous movement in “open field and condition active avoidance reflex in “shuttle box”) and abnormal (choreomyoclonic hyperkinesia, produced by intrastriatal microinjections GABA-A receptors antagonist picrotoxin  2 mcg) motor behavior. 4 mg acetic zinc is used by rats with food ball once a day. 12 mg zinc сonsumption by rats per week did not affected on normal behavior. While 24 mg is produced smaller negative effects on rats reflex performance to 6570% correct responses (of total present during the experiment) but to improved condition avoidance behavior, violated by picrotoxinin rats and reduce the reproducibility of picrotoxin-induced choreo-mioclonic hyperkinesis (human Huntington disease hyperkinesis analog). The influence of zinc on motor behavior depending on its dose and mode of administration is discussed.