| Autor: |
Svetlana Gataullina, Gilles Galvani, Sabrina Touchet, Caroline Nous, Éric Lemaire, Jacques Laschet, Catherine Chiron, Olivier Dulac, Elena Dossi, Jean‐Daniel Brion, Samir Messaoudi, Mouad Alami, Gilles Huberfeld |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
EpilepsiaREFERENCES. 63(11) |
| ISSN: |
1528-1167 |
| Popis: |
Many early-onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific N-methyl-d-aspartate receptor (NMDA-R) subunits is being disentangled as one of the mechanisms of severe early-onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA-R with slow deactivation kinetic results in increased neuronal excitation and synchronization.Starting from an available GluN2C/D antagonist, NMDA-R-modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood-brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1Using a double-electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood-brain barrier was selected. Applied in vivo in six Tsc1Subunit-selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA-R subunit-mediated transmission. |
| Databáze: |
OpenAIRE |
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