Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus

Popis výsledku v původním jazyce

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 &quot;on-demand&quot; 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.

Název v anglickém jazyce

Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus

Popis výsledku anglicky

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 &quot;on-demand&quot; 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30105 - Physiology (including cytology)

Projekt

<a href="/cs/project/NU21-08-00533" target="_blank" >NU21-08-00533: Cílená genová terapie farmakorezistentní fokální epilepsie</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Gene Therapy

ISSN

0969-7128

e-ISSN

1476-5462

Svazek periodika

32

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

15

Strana od-do

106-120

Kód UT WoS článku

001341144300001

EID výsledku v databázi Scopus

2-s2.0-85207366883