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Antagonism of P2X7 receptors enhances lorazepam action in delaying seizure onset in an in vitro model of status epilepticus
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Garcia-Durillo, Monica and Frenguelli, Bruno G. (2023) Antagonism of P2X7 receptors enhances lorazepam action in delaying seizure onset in an in vitro model of status epilepticus. Neuropharmacology, 239 . 109647. doi:10.1016/j.neuropharm.2023.109647 ISSN 0028-3908.
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Official URL: https://doi.org/10.1016/j.neuropharm.2023.109647
Abstract
Approximately 30% of patients with status epilepticus (SE) become refractory to two or more antiseizure medications (ASM). There is thus a real need to identify novel targets to develop new ASMs for treating this clinical emergency. Among purinergic receptors, the ionotropic ATP–gated P2X7 receptor (P2X7R) has received attention as a potential ASM. This study evaluated the effect of the selective P2X7R antagonist A740003 on acute seizures in the dentate gyrus (DG) of hippocampal brain slices, where P2X7Rs are highly expressed, with a view to establishing its potential use as a therapy or adjunct with lorazepam (LZP) in refractory SE. Extracellular field excitatory postsynaptic potentials were recorded from the DG of male mouse hippocampal slices when spontaneous seizure-like events (SLEs) were induced by removing extracellular Mg2+ and sequentially adding the K+ channel blocker 4-aminopyridine and the adenosine A1 receptor antagonist 8-cyclopentyltheophylline. In addition, the early and late combination of A740003 and lorazepam was evaluated. Our study revealed that, in the absence of changes in mRNA for P2X7Rs or inflammatory markers, P2X7R antagonism did not alter the frequency of SLEs. However, A740003 in conjunction with LZP delayed the onset of seizures. Furthermore, our results support the need for employing LZP before seizures become refractory during SE (i.e., in the 60 min frame since first seizure appears) as delayed of application LZP increased seizure frequency. These studies reveal possible sites of intervention that could have a positive impact in patients with high risk of suffering SE or its drug-refractory variant.
Item Type: | Journal Article | ||||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||
Journal or Publication Title: | Neuropharmacology | ||||||||
Publisher: | Elsevier | ||||||||
ISSN: | 0028-3908 | ||||||||
Official Date: | 15 November 2023 | ||||||||
Dates: |
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Volume: | 239 | ||||||||
Article Number: | 109647 | ||||||||
DOI: | 10.1016/j.neuropharm.2023.109647 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||
Date of first compliant deposit: | 14 July 2023 | ||||||||
Date of first compliant Open Access: | 22 August 2023 | ||||||||
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