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 GABA(A) 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.

Automated summary

Neurosteroids and benzodiazepines are GABA(A) receptor modulators with anxiolytic effects. This study aimed to investigate the effects of neurosteroids and their synthesis using a synthetic compound called XBD173, which promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO). The results showed that XBD173 induced neurosteroidogenesis and the application of potentially synthesized neurosteroids did not impair hippocampal CA1-LTP, which is important for learning and memory. Therefore, TSPO ligands could be promising candidates for post-ischemic recovery with neuroprotection and without detrimental effects on synaptic plasticity.