Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F25%3A10486794" target="_blank" >RIV/00216208:11130/25:10486794 - isvavai.cz</a>
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Ui07dQOifo" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Ui07dQOifo</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41434-024-00493-7" target="_blank" >10.1038/s41434-024-00493-7</a>
Alternative languages
Result language
angličtina
Original language name
Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus
Original language description
Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an "on-demand" treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM(817), which selectively activates the chloride-permeable channel PSAM(4)-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM(817) decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM(817) in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM(4)-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30105 - Physiology (including cytology)
Result continuities
Project
<a href="/en/project/NU21-08-00533" target="_blank" >NU21-08-00533: Targeted gene therapy for pharmacoresistant focal epilepsy</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Gene Therapy
ISSN
0969-7128
e-ISSN
1476-5462
Volume of the periodical
32
Issue of the periodical within the volume
2
Country of publishing house
GB - UNITED KINGDOM
Number of pages
15
Pages from-to
106-120
UT code for WoS article
001341144300001
EID of the result in the Scopus database
2-s2.0-85207366883