Antiparkinsonian activity of new N-methyl-D-aspartate receptor ligands in the arecoline hyperkinesis test

Introduction. Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in the population of older patients. Even though long-term combination therapy helps to cope with the main manifestations of PD. It inevitably leads to the appearance of such side effects as drowsiness, hallucinations, dyskinesia, and many others. [12]. Therefore, the search for effective antiparkinsonian drugs devoid of the above-mentioned adverse reactions remains an urgent task of modern neuropharmacology.The explored substances are derivatives of imidazole-4,5-dicarboxylic acid. These compounds belong to a fundamentally new class of N-methyl-D-aspartate ligands (NMDA) that are not channel blockers. Their pharmacological effect is realized due to interaction with the NMDA receptor recognition site, which, along with high efficiency, allows us to assume their higher safety, compared to previously existing channel blockers from the NMDA ligand group.Objective. Studing of the antiparkinsonian activity of new ligands of the glutamate NMDA-receptor complex-1,2-substituted imidazole-4,5-dicarboxylic acids on an experimental model of arecoline hyperkinesis.Materials and methods. Imidazole-dicarboxylic acid derivatives (IEM2258, IEM2248, IEM2247, and IEM1574) were injected into the lateral ventricles of the mouse brain 10 minutes before arecoline in a volume of 5 µl at doses of 0.1-0.5 µmol, then the latent period, intensity, and duration of tremor were recorded. Amantadine was used as a comparison drug.Results. Preliminary administration of the studied examined substances led to a significant decrease in the intensity and duration of arecoline tremor. The highest inhibitory activity with respect to the intensity and duration of the experimental tremor was demonstrated with the introduction of the compound IEM-2247 (at a dose of 0.1-0.5 mmol, the duration of the latent period of the tremor was 1.7-2.3 times longer than the control one, respectively, the duration of the tremor decreased by 1.5 - 2.5 times).Conclusions. The dose-dependent antiparkinsonian activity of imidazole-dicarboxylic acid derivatives is shown, indicating the prospects for the development of these substances and the further search for effective and safe antiparkinsonian agents among the compounds of this class.

Effect 1 of NMDA Receptor Agonist and Antagonist on Nicotine withdrawal induced Hyperexcitability in Mice

Kynurenic acid is a recognized broad-spectrum antagonist of excitatory amino acid receptors with a particularly high affinity for the glycine co-agonist site of the N-methyl-D-aspartate (NMDA) receptor complex. D- Cycloserine is a NMDA receptor partial agonist which facilitate in an initiation of nicotine withdrawal symptoms and dependence. Thus, the influence of kynurenic acid treatment on the development and expression of nicotine dependence was tested by using the nicotine withdrawal-induced hyperexcitability paradigm. Mice were provided with a nutritionally balanced control liquid diet as the sole nutrient source on day 0; from day 1–4 (nicotine 25µg), from day 5–7 (nicotine, 50ug) and from day 8–10 (nicotine, 100ug) was incorporated into the liquid diet. On day 11, the nicotine liquid diet was replaced with nutritionally balanced control liquid diet, and nicotine withdrawal-induced hyperexcitability signs were recorded. The results revealed that acute administration of kunurenic acid (50 and 100mg/kg, i.p.) dose-dependently attenuated nicotine withdrawal-induced hyperexcitability signs, and these results were comparable to D- Cycloserine (50 and 100mg/kg, i.p.) Further, chronic administration of kunurenic acid (50 and 100mg/kg, i.p.) to the nicotine diet fed mice markedly attenuated the nicotine withdrawal-induced hyperexcitability signs. In conclusion, the results and evidence suggest that kinurenic acid exhibited an inhibitory influence against nicotine withdrawal-induced hyperexcitability signs, which could be mediated through its neuromodulatory action.

Early and Delayed Impact of Nanosilver on the Glutamatergic NMDA Receptor Complex in Immature Rat Brain

Silver nanoparticles (AgNPs) are the one of the most extensively used nanomaterials. The strong antimicrobial properties of AgNPs have led to their use in a wide range of medical and consumer products. Although the neurotoxicity of AgNPs has been confirmed, the molecular mechanisms have not been extensively studied, particularly in immature organisms. Based on information gained from previous in vitro studies, in the present work, we examine whether ionotropic NMDA glutamate receptors contribute to AgNP-induced neurotoxicity in an animal model of exposure. In brains of immature rats subjected to a low dose of AgNPs, we identified ultrastructural and molecular alterations in the postsynaptic region of synapses where NMDA receptors are localized as a multiprotein complex. We revealed decreased expression of several NMDA receptor complex-related proteins, such as GluN1 and GluN2B subunits, scaffolding proteins PSD95 and SynGAP, as well as neuronal nitric oxide synthase (nNOS). Elucidating the changes in NMDA receptor-mediated molecular mechanisms induced by AgNPs, we also identified downregulation of the GluN2B-PSD95-nNOS-cGMP signaling pathway which maintains LTP/LTD processes underlying learning and memory formation during development. This observation is accompanied by decreased density of NMDA receptors, as assessed by a radioligand binding assay. The observed effects are reversible over the post-exposure time. This investigation reveals that NMDA receptors in immature rats are a target of AgNPs, thereby indicating the potential health hazard for children and infants resulting from the extensive use of products containing AgNPs.

A Review of the Actions of D-cycloserine, a Putative Nootropic Agent, at the NMDA Receptor Complex-Associated Glycine Binding Site

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Studying the anticonvulsive activity of new ligands of NDMA-receptor complex – imidazole-4,5-dicarbonic acid derivatives

NMDA receptors were proven to play a significant role in the processes of epileptogenesis. Experimental data indicate a significant anticonvulsant effect of NMDA receptor antagonists, but the use of the studied NMDA ligands remains limited due to their low efficiency and toxic effects. The aim of the study was to investigate the anticonvulsant effect of new ligands of the glutamate NMDA receptor complex imidazole-4,5-dicarboxylic acid (IDA) derivatives on a model of NMDA-induced convulsions in mice. The tested agents (IEM2258 and IEM2248) were injected into the lateral ventricles of a waking mouse brain at doses of 0.10.5 mmol in 5 l 15 minutes before the convulsant (NMDA). Valproic acid was used as a comparator drug. The results of the study showed that IDA derivatives exhibit anticonvulsant activity of various degrees of severity. A pronounced anticonvulsant effect was established for IEM2258 at a dose of 0.4 mmol: a significant reduction in the duration of convulsions (compared to the previous dose of the tested substance) and a total absence of NMDA-induced deaths. IEM2248 showed anticonvulsant activity at a dose of 0.2 mmol, in 100% of cases preventing fatal outcomes and completely protecting animals from the convulsions. Thus, the data obtained in this study showed dose-dependent anticonvulsant effect of new IDA derivatives (IEM2258 and IEM2248) due to the blockade of the NMDA receptor complex, that indicates the promising aspect for the development of these agents and further searching for effective and safe anticonvulsants among this pharmacological class.