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. 2022 Mar 18;52(2):308–314. doi: 10.1007/s11055-022-01238-y

Mechanisms of AMPA Receptor Inhibition by Diminazene

A S Zhigulin 1, M Yu Dron 1, O I Barygin 1,✉
PMCID: PMC8930484  PMID: 35317269

Abstract

Diminazene is an anti-infection agent for animals and is a member of the diarylamidine group. This study reports the first detection of its inhibitory effect on AMPA-type ionotropic glutamate receptors. Experiments were carried out on isolated Wistar rat neurons: striatal giant cholinergic interneurons were used to study calcium-permeable AMPA receptors and hippocampal field CA1 pyramidal neurons were used to study calcium-impermeable AMPA receptors. Cells were isolated by vibrodissociation and currents were recorded by voltage clamping in the whole cell configuration. Diminazene produced concentration-dependent inhibition of currents evoked by application of kainate in both neuron types. IC50 values for calcium-permeable and calcium-impermeable AMPA receptors were 60 ± 11 and 160 ± 30 μM, respectively. Of note is that the inhibitory action of diminazene increased with increases in agonist concentration. The plot of the voltage dependence of inhibition at a fixed diminazene concentration for calcium-permeable AMPA receptors was biphasic: minimal inhibition was seen at positive potentials and maximum at –40 to –60 mV, while further hyperpolarization produced a gradual decrease in blockade efficacy. All these properties provide evidence that diminazene blocks AMPA receptor channels, perhaps with penetration through channels into cells.

Keywords: AMPA receptors, diminazene, inhibition mechanisms, patch clamp

Footnotes

Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 107, No. 8, pp. 1039–1048, August, 2021.

References

  • 1.Oliveira GLD, de Freitas RM. Diminazene aceturate – An antiparasitic drug of antiquity: Advances in pharmacology & therapeutics. Pharmacol. Res. 2015;102:138–157. doi: 10.1016/j.phrs.2015.10.005. [DOI] [PubMed] [Google Scholar]
  • 2.Peregrine AS, Mamman M. Pharmacology of diminazene – a review. Acta Trop. 1993;54(3–4):185–203. doi: 10.1016/0001-706x(93)90092-P. [DOI] [PubMed] [Google Scholar]
  • 3.Kuriakose S, Uzonna JE. Diminazene aceturate (Berenil), a new use for an old compound? Int. Immunopharmacol. 2014;21(2):342–345. doi: 10.1016/j.intimp.2014.05.027. [DOI] [PubMed] [Google Scholar]
  • 4.S. Kuriakose, H. M. Muleme, C. Onyilagha, et al., “Diminazene aceturate (Berenil) modulates the host cellular and inflammatory responses to Trypanosoma congolense infection,” PLoS One, 7, No. 11 (2012), 10.1371/journal.pone.0048696. [DOI] [PMC free article] [PubMed]
  • 5.Chen XM, Qiu LY, Li MH, et al. Diarylamidines: High potency inhibitors of acid-sensing ion channels. Neuropharmacology. 2010;58(7):1045–1053. doi: 10.1016/j.neuropharm.2010.01.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Schmidt A, Rosselti G, Joussen S, Grunder S. Towards the molecular basis of ASIC inhibition by diminazene. Acta Physiol. 2017;219:143–143. [Google Scholar]
  • 7.Nicolau LAD, Noleto IRSG, Medeiros JVR. Could a specific ACE2 activator drug improve the clinical outcome of SARSCoV-2? A potential pharmacological insight. Expert Rev. Clin. Phar. 2020;13(8):807–811. doi: 10.1080/17512433.2020.1798760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Dron MY, Zhigulin AS, Barygin LI. Mechanisms of NMDA receptor inhibition by diarylamidine compounds. Eur. J. Neurosci. 2020;51(7):1573–1582. doi: 10.1111/ejn.14589. [DOI] [PubMed] [Google Scholar]
  • 9.Traynelis SF, Wollmuth LP, McBain CJ, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 2010;62(3):405–496. doi: 10.1124/pr.109.002451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Swanson GT, Kamboj SK, CullCandy SG. Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. J. Neurosci. 1997;17(1):58–69. doi: 10.1523/JNEUROSCI.17-01-00058.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Magazanik LG, Buldakova SL, Samoilova MV, et al. Block of open channels of recombinant AMPA receptors and native AMPA/kainate receptors by adamantane derivatives. J. Physiol. 1997;505(3):655–663. doi: 10.1111/j.1469-7793.1997.655ba.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Mellor IR, Usherwood PNR. Targeting ionotropic receptors with polyamine-containing toxins. Toxicon. 2004;43(5):493–508. doi: 10.1016/j.toxicon.2004.02.003. [DOI] [PubMed] [Google Scholar]
  • 13.Barygin OI. Inhibition of calcium-permeable and calcium-impermeable AMPA receptors by perampanel in rat brain neurons. Neurosci. Lett. 2016;633:146–151. doi: 10.1016/j.neulet.2016.09.028. [DOI] [PubMed] [Google Scholar]
  • 14.Fukushima K, Hatanaka K, Sagane K, Ido K. Inhibitory effect of anti-seizure medications on ionotropic glutamate receptors: special focus on AMPA receptor subunits. Epilepsy Res. 2020;167:106452. doi: 10.1016/j.eplepsyres.2020.106452. [DOI] [PubMed] [Google Scholar]
  • 15.Hanada T, Hashizume Y, Tokuhara N, et al. Perampanel: A novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia. 2011;52(7):1331–1340. doi: 10.1111/j.1528-1167.2011.03109.x. [DOI] [PubMed] [Google Scholar]
  • 16.Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol. Scand. 2013;127:19–24. doi: 10.1111/ane.12100). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Vorobjev VS. vibrodissociation of sliced mammalian nervous-tissue. J Neurosci. Methods. 1991;38(2–3):145–150. doi: 10.1016/0165-0270(91)90164-U. [DOI] [PubMed] [Google Scholar]
  • 18.Buldakova SL, Vorobjev VS, Sharonova IN, et al. Characterization of AMPA receptor populations in rat brain cells by the use of subunit-specific open channel blocking drug, IEM-1460. Brain Res. 1999;846(1):52–58. doi: 10.1016/S0006-8993(99)01970-8. [DOI] [PubMed] [Google Scholar]
  • 19.Samoilova MV, Buldakova SL, Vorobjev VS, et al. The open channel blocking drug, IEM-1460, reveals functionally distinct alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors in rat brain neurons. Neuroscience. 1999;94(1):261–268. doi: 10.1016/S0306-4522(99)00326-7. [DOI] [PubMed] [Google Scholar]
  • 20.Tikhonov DB, Samoilova MV, Buldakova SL, et al. Voltage-dependent block of native AMPA receptor channels by dicationic compounds. Br. J. Pharmacol. 2000;129(2):265–274. doi: 10.1038/sj.bjp.0703043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Donevan SD, Rogawski MA. Gyki 52466, a 2,3-benzodiazepine, is a highly selective, noncompetitive antagonist of AMPA/kainate receptor responses. Neuron. 1993;10(1):51–59. doi: 10.1016/0896-6273(93)90241-I. [DOI] [PubMed] [Google Scholar]
  • 22.E. C. Twomey, M. V. Yelshanskaya, A. A. Vassilevski, and A. I. Sobolevsky, “Mechanisms of channel block in calcium-permeable AMPA receptors,” Neuron, 99 (5, 956 (2018), 10.1016/j.neuron.2018.07.027. [DOI] [PMC free article] [PubMed]
  • 23.Bolshakov KV, Kim KH, Potapjeva NN, et al. Design of antagonists for NMDA and AMPA receptors. Neuropharmacology. 2005;49(2):144–155. doi: 10.1016/j.neuropharm.2005.02.007. [DOI] [PubMed] [Google Scholar]
  • 24.Antonov SM, Grishin EV, Magazanik LG, et al. Argiopin blocks the glutamate responses and sensorimotor transmission in motoneurons of isolated frog spinal-cord. Neurosci. Lett. 1987;83(1–2):179–184. doi: 10.1016/0304-3940(87)90237-0. [DOI] [PubMed] [Google Scholar]
  • 25.Barygin OI, Grishin EV, Tilchonov DB. Argiotoxin in the closed AMPA receptor channel: Experimental and modeling study. Biochemistry. 2011;50(38):8213–8220. doi: 10.1021/bi200617v. [DOI] [PubMed] [Google Scholar]
  • 26.Eldefrawi AT, Eldefrawi ME, Konno K, et al. Structure and synthesis of a potent glutamate receptor antagonist in wasp venom. Proc. Natl. Acad. Sci. USA. 1988;85(13):4910–4913. doi: 10.1073/pnas.85.13.4910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Jackson AC, Milstein AD, Soto D, et al. Probing TARP modulation of AMPA receptor conductance with polyamine toxins. J. Neurosci. 2011;31(20):7511–7520. doi: 10.1523/Jneurosci.6688-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Tikhonova TB, Barygin OI, Gmiro VE, et al. Organic blockers escape from trapping in the AMPA receptor channels by leaking into the cytoplasm. Neuropharmacology. 2008;54(4):653–664. doi: 10.1016/j.neuropharm.2007.11.014. [DOI] [PubMed] [Google Scholar]
  • 29.Barygin OI, Luchkina NV, Tikhonov DB. Voltage-dependent and -independent block of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor channels. J. Neurochem. 2010;115(6):1621–1632. doi: 10.1111/j.1471-4159.2010.07068.x.m. [DOI] [PubMed] [Google Scholar]
  • 30.Tikhonova TB, Tikhonov DB, Magazanik LG. Common binding site for externally and internally applied AMPA receptor channel blockers. J. Mol. Neurosci. 2009;39(1–2):169–174. doi: 10.1007/s12031-008-9172-5. [DOI] [PubMed] [Google Scholar]
  • 31.Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch. 2010;460(2):525–542. doi: 10.1007/s00424-010-0809-1. [DOI] [PubMed] [Google Scholar]
  • 32.Zaitsev AV, Kim KK, Fedorova IM, et al. Specific mechanism of use-dependent channel block of calcium-permeable AMPA receptors provides activity-dependent inhibition of glutamatergic neurotransmission. J. Physiol. 2011;589(7):1587–1601. doi: 10.1113/jphysiol.2011.204362. [DOI] [PMC free article] [PubMed] [Google Scholar]

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