Abstract
Perinatal hypoxia can lead to multiple chronic neurological deficits, e.g., mental retardation, behavioral abnormalities, and epilepsy. Levetiracetam (LEV), 2S-(2-oxo-1-pyrrolidiny1) butanamide, is an anticonvulsant drug with proven efficiency in treating patients with focal and generalized seizures. Rats were underwent hypoxia and seizures at the age of 10–12 postnatal days (pd). The ambient level and depolarization-induced exocytotic release of [3H]GABA (γ-aminobutyric acid) were analyzed in nerve terminals in the hippocampus and cortex 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 norm and after perinatal hypoxia. LEV had no effects on the ambient [3H]GABA level. The latter increased during development and was further elevated after perinatal hypoxia in nerve terminals in the hippocampus during the whole period and in the cortex in young adults. Exocytotic [3H]GABA release from nerve terminals increased after perinatal hypoxia during development in the hippocampus and cortex, however this effect was preserved at all ages during blockage of GABA transporters by NO-711 in the hippocampus only. LEV realized its anticonvulsant effects at the presynaptic site through an increase in exocytotic release of GABA. LEV exerted more significant effect after perinatal hypoxia than in norm. Action of LEV was strongly age-dependent and can be registered in puberty and young adults, but the drug was inert at the infantile stage.
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Abbreviations
- GABA:
-
γ-Aminobutyric acid
- pd:
-
Postnatal days
- LEV:
-
Levetiracetam, 2S-(2-oxo-1-pyrrolidiny1)butanamide
- SV2A:
-
Synaptic vesicle membrane protein 2A
- NO-711:
-
1,2,5,6-Tetrahydro-1-(2-(((diphenylmethylene)amino)oxy)ethyl)-3-pyridinecarboxylic acid hydrochloride
- SEM:
-
Standard error of the mean
- ACS:
-
Aqueous counting scintillant
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Acknowledgements
We thank Dr. L.Yatsenko and also appreciate and commemorate contribution of untimely deceased Dr. N.Himmelreich to perinatal hypoxia model development.
Funding
This work was supported by the grants of National Academy of Sciences of Ukraine within the programs “Molecular and cellular biotechnologies for medicine, industry and agriculture” (#35-2019); “Scientific Space Research 2018-2022” (#19-2019); “Smart sensory devices of a new generation based on modern materials and technologies for 2018–2022” (#9/1-2019); State Fund For Fundamental Research (# F76/13-2018); and International bilateral Latvian-Ukrainian cooperative research grant of the Ministry of Education and Science of Ukraine (2019-2020).
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NP and MD performed experimental work; NP and TB contributed experimental data analysis and paper preparation.
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All experimental procedures were conducted according to standard ethical guidelines (European Community Guidelines on the Care and Use of Laboratory Animals 86/609/EEC) and approved by Animal Care and Use Committee of the Palladin Institute of Biochemistry (Protocol from 19/09-2011). All studies involving animals are reported in accordance with the ARRIVE guidelines for reporting experiments involving animals (McGrath et al. 2010).
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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 39, 701–714 (2019). https://doi.org/10.1007/s10571-019-00676-6
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DOI: https://doi.org/10.1007/s10571-019-00676-6