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

by Selleckchem | Mar 13 2023

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 non-convulsive dose of glutamine synthetase (GS) 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 post-stimulus rise of amplitude of Pilo-induced electrographic seizures and their attenuation by MSO are correlated with the release of taurine from seizure-affected hippocampus.

Methods: Lithium pretreated animals were administered MSO (75 mg/kg i.p.) 2.5 h before the induction of convulsions by Pilo (40 mg/kg i.p.). 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, eGln and 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~0.72-0.96) 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>0.92) and moderately (r~ -0.59) with eGln, but not with eGlu.

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

Comments：

In this study, the researchers investigated the mechanism of how pretreatment with a non-convulsive dose of glutamine synthetase (GS) inhibitor methionine sulfoximine (MSO) mitigates the intensity of initial pilocarpine (Pilo)-induced seizures in juvenile rats. The researchers hypothesized that MSO exerts its protective effect by preventing the seizure-initiating and seizure-propagating increase of cell volume. To test this hypothesis, the researchers measured extracellular accumulation of taurine (eTau), an osmosensitive amino acid whose release reflects increased cell volume, in the microdialysates of the ventral hippocampal CA1 region collected at 15 min intervals during the whole 3.5 h observation period.

The results showed that the EEG amplitude across most frequency bands peaked at ~40 min post-Pilo and showed strong temporal correlation with eTau but no correlation with extracellular accumulation of glutamine (eGln) or glutamate (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 and moderately correlated with eGln but not with eGlu. The strong correlation between the attenuation of Pilo-induced seizures and taurine release indicates that the beneficial effect of MSO is due to the prevention of cell volume increase concurrent with the onset of seizures.

Overall, this study provides insight into the mechanism by which MSO exerts its protective effect against Pilo-induced seizures in juvenile rats. By preventing the increase in cell volume concurrent with the onset of seizures, MSO may be able to mitigate the intensity of initial seizures, which could have therapeutic implications for the treatment of epilepsy.