Improved seizure liability detection by combining rat hippocampal brain slice electrophysiology with in vivo behavior observation following intracerebroventricular drug administration.

Autor: Tsubouchi T; Sumitomo Pharma Co., Ltd., Osaka 554-0022, Japan. Electronic address: tadashi.tsubouchi@sumitomo-pharma.co.jp., Ikeda K; Sumitomo Pharma Co., Ltd., Osaka 554-0022, Japan., Sasaki Y; Sumitomo Pharma Co., Ltd., Osaka 554-0022, Japan., Watanabe H; Sumitomo Pharma Co., Ltd., Osaka 554-0022, Japan., Chihara K; Sumitomo Pharma Co., Ltd., Osaka 554-0022, Japan., Miyawaki I; Sumitomo Pharma Co., Ltd., Osaka 554-0022, Japan.
Jazyk: angličtina
Zdroj: Journal of pharmacological and toxicological methods [J Pharmacol Toxicol Methods] 2024 Mar-Apr; Vol. 126, pp. 107496. Date of Electronic Publication: 2024 Mar 02.
DOI: 10.1016/j.vascn.2024.107496
Abstrakt: An adverse effect of drug candidates, seizure is a serious issue in drug development. Improving evaluation systems for seizure liability is crucial for selecting good candidates. Firstly, in vitro electrophysiological measurement by a multielectrode array system in rat hippocampal brain slices was employed to confirm an increase in electrically evoked population spike (PS) area, the occurrence of multiple population spikes (MPSs), and thereby the seizure liability of five positive control chemicals: picrotoxin, 4-aminopyridine, pentylenetetrazole, penicillin G, and chlorpromazine. Aspirin, a negative control, did not affect PS area or generate MPSs. Furthermore, baclofen, an anticonvulsant drug, decreased PS area and inhibited the increase in PS area or occurrence of MPSs induced by picrotoxin. A comparative study of seizure liability among carbapenem antibiotics revealed that tienam > carbenin > omegacin and finibax. Despite leading to a strong decrease in PS area, physostigmine, cisplatin, and paroxetine still produced MPSs. Therefore, the increase in PS area or the occurrence of the MPS are considered significant evaluation parameters for seizure liability. In contrast, the in vitro electrophysiological measurement could not detect the seizure liability of diphenhydramine or fluvoxamine. A follow-up study of in vivo mouse behavioral change induced by intracerebroventricular administration of these drugs clearly detected convulsions. The in vitro electrophysiological study using hippocampal brain slices combined with in vivo behavior observation study of drug candidates administered by intracerebroventricular injection can implement to assess the seizure liability of even small amounts, especially in the early stages of drug development.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: