Reviews on Clinical Pharmacology and Drug TherapyReviews on Clinical Pharmacology and Drug Therapy1683-41002542-1875Eco-Vector4240410.17816/RCF182149-154Research ArticleStudying the anticonvulsive activity of new ligands of NDMA-receptor complex – imidazole-4,5-dicarbonic acid derivativesJakovlevaEkaterina E.<p>PhD, Scientific Researcher of The Laboratory of Chemistry and Pharmacology of Pharmaceutical Drug of S.V. Anichkov Department of Neuropharmacology</p>eeiakovleva@mail.ruFokshaStanislav P.<p>PhD Student, S.V. Anichkov Department of Neuropharmacology</p>dr.foksha@mail.ruBrusinaMarija A.<p>PhD, Junior Scientific Researcher of The Laboratory for the synthesis and nanotechnology of drugs of S.V. Anichkov Department of Neuropharmacology</p>mashasemen@gmail.comKubarskajaLarisa G.<p>PhD, Leading Engineer, S.V. Anichkov Department of Neuropharmacology; Senior Researcher</p>larkub@yandex.ruPiotrovskijLevon B.<p>Doctor of Biological Sciences, Professor, Head of The Laboratory for the synthesis and nanotechnology of drugs of S.V. Anichkov Department of Neuropharmacology</p>piotrovsky@yandex.ruBychkovEugenii R.<p>PhD, Head of The Laboratory of Chemistry and Pharmacology of Pharmaceutical Drugs of S.V. Anichkov Department of Neuropharmacology; Lecturer Department of Pharmacology</p>bychkov@mail.ruShabanovPetr D.<p>Dr. Med. Sci. (Pharmacology), Professor and Head, Dept. of Neuropharmacology</p>pdshabanov@mail.ruInstitute of Experimental MedicineInstitute of Toxicology, Federal Medical and Biological AgencyS.M. Kirov Military Medical Academy160820201821491541608202016082020Copyright © 2020, Jakovleva E.E., Foksha S.P., Brusina M.A., Kubarskaja L.G., Piotrovskij L.B., Bychkov E.R., Shabanov P.D.2020<p>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.</p>glutamateNMDA receptor antagonistsimidazole-4,5-dicarboxylic acid derivativesanticonvulsant effectmiceглутаматантагонисты NMDA-рецепторовпроизводные имидазол-4,5-дикарбоновых кислотпротивосудорожное действиемыши[Беспалов А.Ю., Звартау Э.Э. Нейрофармакология антагонистов NMDA-рецепторов. – СПб.: Невский диалект, 2000. – 297 с. [Bespalov AYu, Zvartau EE. Neyrofarmakologiya antagonistov NMDA-retseptorov. Saint Petersburg: Nevskiy dialekt; 2000. 297 р. (In Russ.)]][Ефремов О.М., Александрова И.Я., Куликов С.В., и др. Влияние ряда производных имидазол-4,5-дикарбоновой кислоты на активность рецепторов N-метил-D-аспарагиновой кислоты (NMDA) // Экспериментальная и клиническая фармакология. – 2005. – Т. 68. – № 1. – С. 7–9. [Efremov OM, Aleksandrova IYa, Kulikov SV, et al. Effect of some imidazole-4,5-dicarboxylic acid derivatives on the activity of N-methyl-D-aspartate (NMDA) receptors. Experimental and clinical pharmacology. 2005;68(1):7-9. (In Russ.)]. https://doi.org/10.30906/0869-2092-2005-68-1-7-9.][Липатова Л.В., Дубинина Е.Е., Алексеева Д.В., и др. Роль окислительного стресса в патогенезе эпилепсии // Сибирское медицинское обозрение. – 2017. – № 1. – С. 11–16. [Lipatova LV, Dubinina EE, Alekseeva DV. The role of oxidative stress in the pathogenesis of epilepsy. Sibirskoe medicinskoe obozrenie. 2017;(1):11-16. (In Russ.)]. https://doi.org/10.20333/2500136-2017-1-11-16.][Зайцев А.В., Ким К.Х., Фролова Е.В., и др. Противосудорожное действие антагонистов NMDA и кальций проницаемых AMPA рецепторов при использовании модели максимального электрошока у крыс // Нейрохимия. – 2014. – Т. 31. – № . 4. – С. 335. [Zaytsev AV, Kim KKh, Frolova EV, et al. Protivosudorozhnoye deystviye antagonistov NMDA i kal’tsiy pronitsayemykh AMPA retseptorov pri ispol’zovanii modeli maksimal’nogo elektroshoka u krys. Neyrokhimiya. 2014;31(4):335. (In Russ.)]. https://doi.org/10.7868/S102781331404013X.][Перфилова В.Н., Тюренков И.Н. Глутаматные ионотропные рецепторы: структура, локализация, функции // Успехи физиологических наук. – 2016. – Т. 47. – № 1. – С. 80–96. [Perfilova VN, Tyurenkov IN. Glutamate ionotropic receptors: structure, localization, functions. Uspekhi fiziologicheskikh nauk. 2016;47(1):80-96. (In Russ.)]][Смоленский В.И., Овсепян С.В., Зайцев А.В. Транспортеры глутамата (ЕААТ-1–3) как фактор патогенеза и перспективная терапевтическая мишень при эпилепсии // Российский физиологический журнал им. И.М. Сеченова. – 2019. – Т. 105. – № 9. – С. 1096–1112. [Smolensky IV, Ovsepian SV, Zaitsev AV. Glutamate transporters (EAATs 1–3) as contributors to the pathogenesisand promising therapeutic targets in epilepsy. Rossiyskiy fiziologicheskiy zhurnal im. I.M. Sechenova. 2019;105(9):1096-1112. (In Russ.)]. https://doi.org/10.1134/S0869813919090097.][Хабриев Р.У. Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ. 2-изд., перераб. и доп. – М.: Медицина, 2005. – 832 с. [Habriev RU. Rukovodstvo po eksperimental’nomu (doklinicheskomu) izucheniyu novykh farmakologicheskikh veshchestv. 2nd revised and updated. Moscow: Meditsina; 2005. 832 р. (In Russ.)]][Bruno V, Caraci F, Copani A, et al. The impact of metabotropic glutamate receptors into active neurodegenerative processes: a bdark side in the development of new symptomatic treatments for neurologic and psychiatric disorders. Neuropharmacol. 2017;115:180-192. https://doi.org/10.1016/j.neuropharm.2016.04.044.][Casillas-Espinosa PM, Powell KL, O’Brien TJ. Regulators of synaptic transmission: roles in the pathogenesis and treatment of epilepsy. Epilepsia. 2012;53(9):41-58. https://doi.org/10.1111/epi.12034.][Chao XD, Fei F, Fei Z. The role of excitatory amino acid transporters in cerebral ischemia. Neurochem Res. 2010;35(8): 1224-1230. https://doi.org/10.1007/s11064-010-0178-3.][Eid T, Gruenbaum SE, Dhaher R, et al. The glutamate-glutamine cycle in epilepsy. Adv Neurobiol. 2016;13:351-400. https://doi.org/10.1007/978-3-319-45096-4_14.][Hanrahan B, Abbasy MS, Carson RP. Felbamate. StatPearls [Internet]. StatPearls Publishing; 2020.][Herrmann EK, Hahn K, Kratzer C. Status epilepticus as a risk factor for postencephalitic parenchyma loss evaluated by ventricle brain ratio measurement on MR imaging. AJNR Am J Neuroradiol. 2006;27(6):1245-1251.][Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 2005;179(1):4-29. https://doi.org/10.1007/s00213-005-2200-z.][Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78(18):1408-1415. https://doi.org/10.1212/WNL.0b013e318254473a.][Lapin IP. Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. J Neural Transmision. 1978;42(1):37-43. https://doi.org/10.1007/BF01262727.][Mehta A, Prabhakar M, Kumar P, et al. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur J Pharmacol. 2013;698(1-3):6-18. https://doi.org/10.1016/j.ejphar.2012.10.032.][Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5(7):553-564. https://doi.org/10.1038/nrn1430.][Shi LL, Dong J, Ni H, et al. Felbamate as an add-on therapy for refractory partial epilepsy. Cochrane Database Syst Rev. 2017;7(7): CD008295. https://doi.org/10. 1002/14651858.CD008295.pub4.][Singh K, Shah YD, Luciano D, et al. Safety and efficacy of perampanel in children and adults with various epilepsy syndromes: a single-center postmarketing study. Epilepsy Behav. 2016;61:41-45. https://doi.org/10.1016/j.yebeh.2016.05.007.][Szydlowska K, Tymianski M. Calcium, ischemia and excitotoxicity. Cell Calcium. 2010;47(2):122-129. https://doi.org/10.1016/j.ceca.2010.01.003.][Traynelis SF, Wollmuth LP, McBain CJ, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010;62(3):405-496. https://doi.org/10.1124/pr.109.002451.][Van der Staay FJ, Rutten K, Erb C, Blokland A. Effects of the cognition impairer MK-801 on learning and memory in mice and rats. Behav Brain Res. 2011;220(1):215-229. https://doi.org/10.1016/j.bbr.2011.01.052.][Wesnes KA, Edgar C, Dean AD, Wroe SJ. The cognitive and psychomotor effects of remacemide and carbamazepine in newly diagnosed epilepsy. Epilepsy Behav. 2009;14(3):522-528. https://doi.org/10.1016/j.yebeh. 2008.11.012.][Zaitsev AV, Kim KKh, Vasilev DS, et al. N-methyl-D-aspartate receptor channel blockers prevent pentylenetetrazole-induced convulsions and morphological changes in rat brain neurons. J Neurosci Res. 2015;93(3):454-465. https://doi.org/10.1002/jnr.23500.]