Ukr.Biochem.J. 2022; Volume 94, Issue 5, Sep-Oct, pp. 28-39

doi: https://doi.org/10.15407/ubj94.05.028

Perinatal hypoxia and thalamus brain region: increased efficiency of antiepileptic drug levetiracetam to inhibit GABA release from nerve terminals

06.12.2022   Uncategorized   No comments

M. V. Dudarenko*, N. G. Pozdnyakova

Department of Neurochemistry, Palladin Institute of Biochemistry,
National Academy of Sciences of Ukraine, Kyiv;
*e-mail: marina.dudarenko@gmail.com

Received: 28 January 2022; Revised: 25 March 2022;
Accepted: 20 September 2022; Available on-line: 19 December 2022

Levetiracetam (LV), 2S-(2-oxo-1-pyrrolidiny1) butanamide, is an antiepileptic drug. The exact mechanisms of anticonvulsant effects of LV remain unclear. In this study, rats (Wistar strain) underwent hypoxia and seizures at the age of 10–12 postnatal days (pd). [3H]GABA release was analysed in isolated from thalamus nerve terminals (synaptosomes) during development at the age of pd 17–19 and pd 24–26 (infantile stage), pd 38–40 (puberty) and pd 66–73 (young adults) in control and after perinatal hypoxia. The extracellular level of [3H]GABA in the preparation of thalamic synaptosomes increased during development at the age of pd 38–40 and pd 66–73 as compared to earlier ones. LV did not influence the extracellular level of [3H]GABA in control and after perinatal hypoxia at all studied ages. Exocytotic [3H]GABA release in control increased at the age of pd 24–26 as compared to pd 17–19. After hypoxia, exocytotic [3H]GABA release from synaptosomes also increased during development. LV elevated [3H]GABA release from thalamic synaptosomes at the age of pd 66–73 after hypoxia and during blockage of GABA uptake by NO-711 only. LV realizes its antiepileptic effects at the presynaptic site through an increase in exocytotic release of [3H]GABA in thalamic synaptosomes after perinatal hypoxia at pd 66–73. LV exhibited a more significant effect in thalamic synaptosomes after perinatal hypoxia than in control ones. The action of LV is age-dependent, and the drug was inert at the infantile stage that can be useful for an LV application strategy in child epilepsy therapy.

Keywords: , , , , ,

References:

  1. Devor A, Ulbert I, Dunn AK, Narayanan SN, Jones SR, Andermann ML, Boas DA, Dale AM. Coupling of the cortical hemodynamic response to cortical and thalamic neuronal activity. Proc Natl Acad Sci USA. 2005;102(10):3822-3827. PubMed, PubMedCentral, CrossRef
  2. Poulet JFA, Fernandez LMJ, Crochet S, Petersen CCH. Thalamic control of cortical states. Nat Neurosci. 2012;15(3):370-372. PubMed, CrossRef
  3. Lüttjohann A, van Luijtelaar G. Dynamics of networks during absence seizure’s on- and offset in rodents and man. Front Physiol. 2015;6:16. PubMed, PubMedCentral, CrossRef
  4. Steriade M. The GABAergic reticular nucleus: a preferential target of corticothalamic projections. Proc Natl Acad Sci USA. 2001;98(7):3625-3627. PubMed, PubMedCentral, CrossRef
  5. Just N, Sonnay S. Investigating the Role of Glutamate and GABA in the Modulation of Transthalamic Activity: A Combined fMRI-fMRS Study. Front Physiol. 2017;8:30. PubMed, PubMedCentral, CrossRef
  6. Paz JT, Huguenard JR. Microcircuits and their interactions in epilepsy: is the focus out of focus? Nat Neurosci. 2015;18(3):351-359. PubMed, PubMedCentral, CrossRef
  7. Makinson CD, Tanaka BS, Sorokin JM, Wong JC, Christian CA, Goldin AL, Escayg A, Huguenard JR. Regulation of Thalamic and Cortical Network Synchrony by Scn8a. Neuron. 2017;93(5):1165-1179.e6. PubMed, PubMedCentral, CrossRef
  8. Klein PM, Lu AC, Harper ME, McKown HM, Morgan JD, Beenhakker MP. Tenuous Inhibitory GABAergic Signaling in the Reticular Thalamus. J Neurosci. 2018;38(5):1232-1248. PubMed, PubMedCentral, CrossRef
  9. Long Z, Li XR, Xu J, Edden RAE, Qin WP, Long LL, Murdoch JB, Zheng W, Jiang YM, Dydak U. Thalamic GABA predicts fine motor performance in manganese-exposed smelter workers. PLoS One. 2014;9(2):e88220. PubMed, PubMedCentral, CrossRef
  10. Zhang C, Chen RX, Zhang Y, Wang J, Liu FY, Cai J, Liao FF, Xu FQ, Yi M, Wan Y. Reduced GABAergic transmission in the ventrobasal thalamus contributes to thermal hyperalgesia in chronic inflammatory pain. Sci Rep. 2017;7:41439. PubMed, PubMedCentral, CrossRef
  11. Halassa MM, Chen Z, Wimmer RD, Brunetti PM, Zhao S, Zikopoulos B, Wang F, Brown EN, Wilson MA. State-dependent architecture of thalamic reticular subnetworks. Cell. 2014;158(4):808-821. PubMed, PubMedCentral, CrossRef
  12. Gschwind M, Seeck M. Modern management of seizures and epilepsy. Swiss Med Wkly. 2016;146:w14310. PubMed, CrossRef
  13. Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U, Levetiracetam N01057 Study Group. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology. 2007;69(18):1751-1760. PubMed, CrossRef
  14. Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia. 2000;41(10):1276-1283. PubMed, CrossRef
  15. De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: the profile of a novel anticonvulsant drug-part I: preclinical data. CNS Drug Rev. 2007;13(1):43-56. PubMed, PubMedCentral, CrossRef
  16. Stout KA, Dunn AR, Hoffman C, Miller GW. The Synaptic Vesicle Glycoprotein 2: Structure, Function, and Disease Relevance. ACS Chem Neurosci. 2019;10(9):3927-3938. PubMed, CrossRef
  17. Bajjalieh SM, Frantz GD, Weimann JM, McConnell SK, Scheller RH. Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J Neurosci. 1994;14(9):5223-5235. PubMed, PubMedCentral, CrossRef
  18. Gillard M, Fuks B, Michel P, Vertongen P, Massingham R, Chatelain P. Binding characteristics of [3H]ucb 30889 to levetiracetam binding sites in rat brain. Eur J Pharmacol. 2003;478(1):1-9. PubMed, CrossRef
  19. Fuks B, Gillard M, Michel P, Lynch B, Vertongen P, Leprince P, Klitgaard H, Chatelain P. Localization and photoaffinity labelling of the levetiracetam binding site in rat brain and certain cell lines. Eur J Pharmacol. 2003;478(1):11-19. PubMed, CrossRef
  20. Tang Y, Yu X, Zhang X, Xia W, Wu X, Zou X, Li H, Huang X, Stefan H, ChenQ, Gong Q, Zhou D. Single-dose intravenous administration of antiepileptic drugs induces rapid and reversible remodeling in the brain: Evidence from a voxel-based morphometry evaluation of valproate and levetiracetam in rhesus monkeys. Neuroscience. 2015;303:595-603. PubMed, CrossRef
  21. Rigo JM, Hans G, Nguyen L, Rocher V, Belachew S, Malgrange B, Leprince P, Moonen G, Selak I, Matagne A, Klitgaard H. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol. 2002;136(5):659-672. PubMed, PubMedCentral, CrossRef
  22. Wakita M, Kotani N, Kogure K, Akaike N. Inhibition of excitatory synaptic transmission in hippocampal neurons by levetiracetam involves Zn²⁺-dependent GABA type A receptor-mediated presynaptic modulation. J Pharmacol Exp Ther. 2014;348(2):246-259. PubMed, CrossRef
  23. Pichardo Macías LA, Ramírez Mendiola BA, Contreras Garcia IJ, Zamudio Hernández SR, Chávez Pacheco JL, Sánchez Huerta KB, Mendoza Torreblanca JG. Effect of levetiracetam on extracellular amino acid levels in the dorsal hippocampus of rats with temporal lobe epilepsy. Epilepsy Res. 2018;140:111-119. PubMed, CrossRef
  24. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther. 2000;85(2):77-85. PubMed, CrossRef
  25. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34(3):453-468. PubMed, CrossRef
  26. Kotsopoulos IAW, van Merode T, Kessels FGH, de Krom MCTFM, Knottnerus JA. Systematic review and meta-analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia. 2002;43(11):1402-1409. PubMed, CrossRef
  27. Briggs SW, Galanopoulou AS. Altered GABA signaling in early life epilepsies. Neural Plast. 2011;2011:527605. PubMed, PubMedCentral, CrossRef
  28. Jensen FE, Wang C, Stafstrom CE, Liu Z, Geary C, Stevens MC. Acute and chronic increases in excitability in rat hippocampal slices after perinatal hypoxia in vivo. J Neurophysiol. 1998;79(1):73-81. PubMed, CrossRef
  29. Sanchez RM, Ribak CE, Shapiro LA. Synaptic connections of hilar basal dendrites of dentate granule cells in a neonatal hypoxia model of epilepsy. Epilepsia. 2012;53(Suppl 1):98-108. PubMed, CrossRef
  30. Rakhade SN, Zhou C, Aujla PK, Fishman R, Sucher NJ, Jensen FE. Early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures. J Neurosci. 2008;28(32):7979-7990. PubMed, PubMedCentral, CrossRef
  31. Pozdnyakova N. Consequences of perinatal hypoxia in developing brain: Changes in GABA transporter functioning in cortical, hippocampal and thalamic rat nerve terminals. Int J Dev Neurosci. 2017;63:1-7. PubMed, CrossRef
  32. Pozdnyakova N, Dudarenko M, Borisova T. Age-Dependency of Levetiracetam Effects on Exocytotic GABA Release from Nerve Terminals in the Hippocampus and Cortex in Norm and After Perinatal Hypoxia. Cell Mol Neurobiol. 2019;39(5):701-714. PubMed, CrossRef
  33. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, NC3Rs Reporting Guidelines Working Group. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160(7):1577-1579. PubMed, PubMedCentral, CrossRef
  34. McGrath JC, Drummond GB, McLachlan EM, Kilkenny C, Wainwright CL. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol. 2010;160(7):1573-1576. PubMed, PubMedCentral, CrossRef
  35. Tarasenko AS, Sivko RV, Krisanova NV, Himmelreich NH, Borisova TA. Cholesterol depletion from the plasma membrane impairs proton and glutamate storage in synaptic vesicles of nerve terminals. J Mol Neurosci. 2010;41(3):358-367. PubMed, CrossRef
  36. Soldatkin O, Nazarova A, Krisanova N, Borysov A, Kucherenko D, Kucherenko I, Pozdnyakova N, Soldatkin A, Borisova T. Monitoring of the velocity of high-affinity glutamate uptake by isolated brain nerve terminals using amperometric glutamate biosensor. Talanta. 2015;135:67-74. PubMed, CrossRef
  37. Larson E, Howlett B, Jagendorf A. Artificial reductant enhancement of the Lowry method for protein determination. Anal Biochem. 1986;155(2):243-248. PubMed, CrossRef
  38. Pozdnyakova N, Pastukhov A, Dudarenko M, Galkin M, Borysov A, Borisova T. Neuroactivity of detonation nanodiamonds: dose-dependent changes in transporter-mediated uptake and ambient level of excitatory/inhibitory neurotransmitters in brain nerve terminals. J Nanobiotechnology. 2016;14:25. PubMed, PubMedCentral, CrossRef
  39. Krisanova N, Pozdnyakova N, Pastukhov A, Dudarenko M, Maksymchuk O, Parkhomets P, Sivko R, Borisova T. Vitamin D3 deficiency in puberty rats causes presynaptic malfunctioning through alterations in exocytotic release and uptake of glutamate/GABA and expression of EAAC-1/GAT-3 transporters. Food Chem Toxicol. 2019;123:142-150. PubMed, CrossRef
  40. Borisova T, Krisanova N, Sivko R, Borysov A. Cholesterol depletion attenuates tonic release but increases the ambient level of glutamate in rat brain synaptosomes. Neurochem Int. 2010;56(3):466-478. PubMed, CrossRef
  41. Borisova T. Express assessment of neurotoxicity of particles of planetary and interstellar dust. NPJ Microgravity. 2019;5:2. PubMed, PubMedCentral, CrossRef
  42. Borisova T. Nervous System Injury in Response to Contact With Environmental, Engineered and Planetary Micro- and Nano-Sized Particles. Front Physiol. 2018;9:728. PubMed, PubMedCentral, CrossRef
  43. Borisova T. Permanent dynamic transporter-mediated turnover of glutamate across the plasma membrane of presynaptic nerve terminals: arguments in favor and against. Rev Neurosci. 2016;27(1):71-81. PubMed, CrossRef
  44. Borisova T, Borysov A, Pastukhov A, Krisanova N. Dynamic Gradient of Glutamate Across the Membrane: Glutamate/Aspartate-Induced Changes in the Ambient Level of L-[14C]glutamate and D-[3H]aspartate in Rat Brain Nerve Terminals. Cell Mol Neurobiol. 2016;36(8):1229-1240. PubMed, CrossRef
  45. Borisova T, Borysov A. Putative duality of presynaptic events. Rev Neurosci. 2016;27(4):377-383. PubMed, CrossRef
  46. Kilb W. Development of the GABAergic system from birth to adolescence. Neuroscientist. 2012;18(6):613-630. PubMed, CrossRef
  47. Coyle JT, Enna SJ. Neurochemical aspects of the ontogenesis of GABAnergic neurons in the rat brain. Brain Res. 1976;111(1):119-133. PubMed, CrossRef
  48. Wong PT, McGeer EG. Postnatal changes of GABAergic and glutamatergic parameters. Brain Res. 1981;227(4):519-529. PubMed, CrossRef
  49. Takayama C, Inoue Y. Developmental expression of GABA transporter-1 and 3 during formation of the GABAergic synapses in the mouse cerebellar cortex. Brain Res Dev Brain Res. 2005;158(1-2):41-49. PubMed, CrossRef
  50. Vitellaro-Zuccarello L, Calvaresi N, De Biasi S. Expression of GABA transporters, GAT-1 and GAT-3, in the cerebral cortex and thalamus of the rat during postnatal development. Cell Tissue Res. 2003;313(3):245-257. PubMed, CrossRef
  51. Avila MAN, Real MA, Guirado S. Patterns of GABA and GABA Transporter-1 immunoreactivities in the developing and adult mouse brain amygdala. Brain Res. 2011;1388:1-11. PubMed, CrossRef
  52. Pozdnyakova N, Yatsenko L, Parkhomenko N, Himmelreich N. Perinatal hypoxia induces a long-lasting increase in unstimulated gaba release in rat brain cortex and hippocampus. The protective effect of pyruvate. Neurochem Int. 2011;58(1):14-21. PubMed, CrossRef
  53. Rambeck B, Jürgens UH, May TW, Pannek HW, Behne F, Ebner A, Gorji A, Straub H, Speckmann EJ, Pohlmann-Eden B, Löscher W. Comparison of brain extracellular fluid, brain tissue, cerebrospinal fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy. Epilepsia. 2006;47(4):681-694. PubMed, CrossRef
  54. Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol. 2009;5(7):380-391. PubMed, PubMedCentral, CrossRef
  55. Takamori S, Riedel D, Jahn R. Immunoisolation of GABA-specific synaptic vesicles defines a functionally distinct subset of synaptic vesicles. J Neurosci. 2000;20(13):4904-4911. PubMed, PubMedCentral, CrossRef
  56. Grønborg M, Pavlos NJ, Brunk I, Chua JJE, Münster-Wandowski A, Riedel D, Ahnert-Hilger G, Urlaub H, Jahn R. Quantitative comparison of glutamatergic and GABAergic synaptic vesicles unveils selectivity for few proteins including MAL2, a novel synaptic vesicle protein. J Neurosci. 2010;30(1):2-12. PubMed, PubMedCentral, CrossRef
  57. Perucca E, Johannessen SI. The ideal pharmacokinetic properties of an antiepileptic drug: how close does levetiracetam come? Epileptic Disord. 2003;5(Suppl 1):S17-S26. PubMed
  58. Kim J, Kondratyev A, Gale K. Antiepileptic drug-induced neuronal cell death in the immature brain: effects of carbamazepine, topiramate, and levetiracetam as monotherapy versus polytherapy. J Pharmacol Exp Ther. 2007;323(1):165-173. PubMed, PubMedCentral, CrossRef
  59. Velíšková J, Moshé SL. Sexual dimorphism and developmental regulation of substantia nigra function. Ann Neurol. 2001;50(5):596-601. PubMed, CrossRef
  60. Sperber EF, Velísková J, Germano IM, Friedman LK, Moshé SL. Age-dependent vulnerability to seizures. Adv Neurol. 1999;79:161-169. PubMed
Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.