亚砜亚甲基-L-蛋氨酸预处理可减弱匹罗卡品诱导的初始电发作，与海马区细胞外牛磺酸的减少密切相关。

Attenuation of initial pilocarpine-induced electrographic seizures by methionine sulfoximine pretreatment tightly correlates with the reduction of extracellular taurine in the hippocampus.

机构信息

Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.

Institute of Theory of Electrical Engineering, Measurement, and Information Systems, Warsaw University of Technology, Warsaw, Poland.

出版信息

Epilepsia. 2023 May;64(5):1390-1402. doi: 10.1111/epi.17554. Epub 2023 Mar 15.

DOI:10.1111/epi.17554

PMID:36808593

Abstract

OBJECTIVE

Initiation and development of early seizures by chemical stimuli is associated with brain cell swelling resulting in edema of seizure-vulnerable brain regions. We previously reported that pretreatment with a nonconvulsive dose of glutamine (Gln) synthetase inhibitor methionine sulfoximine (MSO) mitigates the intensity of initial pilocarpine (Pilo)-induced seizures in juvenile rats. We hypothesized that MSO exerts its protective effect by preventing the seizure-initiating and seizure-propagating increase of cell volume. Taurine (Tau) is an osmosensitive amino acid, whose release reflects increased cell volume. Therefore, we tested whether the poststimulus rise of amplitude of Pilo-induced electrographic seizures and their attenuation by MSO are correlated with the release of Tau from seizure-affected hippocampus.

METHODS

Lithium-pretreated animals were administered MSO (75 mg/kg ip) 2.5 h before the induction of convulsions by Pilo (40 mg/kg ip). Electroencephalographic (EEG) power was analyzed during 60 min post-Pilo, at 5-min intervals. Extracellular accumulation of Tau (eTau) served as a marker of cell swelling. eTau, extracellular Gln (eGln), and extracellular glutamate (eGlu) were assayed in the microdialysates of the ventral hippocampal CA1 region collected at 15-min intervals during the whole 3.5-h observation period.

RESULTS

The first EEG signal became apparent at ~10 min post-Pilo. The EEG amplitude across most frequency bands peaked at ~40 min post-Pilo, and showed strong (r ~ .72-.96) temporal correlation with eTau, but no correlation with eGln or eGlu. MSO pretreatment delayed the first EEG signal in Pilo-treated rats by ~10 min, and depressed the EEG amplitude across most frequency bands, to values that remained strongly correlated with eTau (r > .92) and moderately correlated (r ~ -.59) with eGln, but not with eGlu.

SIGNIFICANCE

Strong correlation between attenuation of Pilo-induced seizures and Tau release indicates that the beneficial effect of MSO is due to the prevention of cell volume increase concurrent with the onset of seizures.

摘要

目的

化学刺激引发的早期癫痫发作和脑细胞肿胀有关，进而导致癫痫易损脑区水肿。我们先前的研究报道，使用非惊厥剂量的谷氨酰胺合成酶抑制剂（MSO）预处理可以减轻幼鼠匹罗卡品（Pilo）诱导癫痫发作的强度。我们假设 MSO 通过防止起始性和传播性的细胞体积增加来发挥其保护作用。牛磺酸（Tau）是一种渗透压敏感的氨基酸，其释放反映了细胞体积的增加。因此，我们测试了刺激后 Pilo 诱导的脑电图痫性发作幅度的升高以及 MSO 对其的衰减是否与受痫影响的海马 Tau 的释放有关。

方法

锂预处理动物在匹罗卡品（40mg/kg，ip）诱导惊厥前 2.5 小时给予 MSO（75mg/kg，ip）。在匹罗卡品后 60 分钟内每隔 5 分钟分析脑电图（EEG）功率。细胞肿胀的标志物是细胞外 Tau（eTau）的积累。在整个 3.5 小时的观察期间，每隔 15 分钟收集腹侧海马 CA1 区的微透析液，测定细胞外 Gln（eGln）和细胞外谷氨酸（eGlu）以及 Tau（eTau）。

结果

在匹罗卡品后约 10 分钟出现了第一个 EEG 信号。在匹罗卡品后约 40 分钟，大多数频带的 EEG 幅度达到峰值，与 eTau 呈强相关性（r .72-.96），但与 eGln 或 eGlu 无相关性。MSO 预处理使匹罗卡品处理大鼠的第一个 EEG 信号延迟了约 10 分钟，并使大多数频带的 EEG 幅度降低，其与 eTau 仍保持强烈相关性（r>.92），与 eGln 中度相关（r-.59），但与 eGlu 无关。