ERK1/2 kinases and dopamine D2 receptors participate in the anticonvulsant effects of a new derivative of benzoylpyridine oxime and valproic acid.

Inhibition of the activity of extracellular signal-regulated kinases (ERK1/2) induced by the activation of the dopamine D2 receptor signalling cascade may be a promising pharmacological target. The aim of this work was to study the involvement of ERK1/2 and dopamine D2 receptor in the mechanism of the anticonvulsant action of valproic acid (VA) and a new benzoylpyridine oxime derivative (GIZH-298), which showed antiepileptic activity in different models of epilepsy. We showed that subchronic exposure to maximal electroshock seizures (MES) for 5 days reduced the density of dopamine D2 receptors in the striatum of mice. GIZH-298 counteracted the decrease in the number of dopamine D2 receptors associated with MES and increased the number of ligand binding sites of dopamine D2 receptors in mice without MES. The affinity of dopamine D2 receptors to the ligand was not changed by GIZH-298. MES caused an increase in ERK1/2 and synapsin I phosphorylation in the striatum while GIZH-298, similar to VA, reduced the levels of both phospho-ERK1/2 and phosphosynapsin I after MES, which correlated with the decrease in the intensity of seizure in mice. In addition, GIZH-298 suppressed ERK1/2 phosphorylation in SH-SY5Y human neuroblastoma cells at therapeutic concentrations, while VA inhibited ERK1/2 phosphorylation in vivo but not in vitro. The data obtained expand the understanding of the mechanisms of action of VA and GIZH-298, which involve regulating the activity of ERK1/2 kinases, probably by modulating dopamine D2 receptors in limbic structures, as well as (in the case of GIZH-298) directly inhibiting of the ERK1/2 cascade.

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.