Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABAA Receptors without Affecting Synaptic Plasticity

Neurosteroids and benzodiazepines are modulators of the GABAA receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked...

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Published in:International journal of molecular sciences 2023-05, Vol.24 (10), p.9056
Main Authors: Puig-Bosch, Xènia, Ballmann, Markus, Bieletzki, Stefan, Antkowiak, Bernd, Rudolph, Uwe, Zeilhofer, Hanns Ulrich, Rammes, Gerhard
Format: Article
Language:English
Subjects:
Animal cognition
Benzodiazepines
Cognition
Cognitive ability
Excitotoxicity
GABAA receptors
Hippocampus
Hypoglycemia
Hypoxia
Ischemia
Ligands
Long-term potentiation
LTP
Memory
Midazolam
Neuromodulation
Neuroprotection
Neurosteroidogenesis
Neurosteroids
Physiology
Pregnanolone
Proteins
Side effects
Synaptic plasticity
Traumatic brain injury
γ-Aminobutyric acid A receptors
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Summary:Neurosteroids and benzodiazepines are modulators of the GABAA receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms24109056