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 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.
FEB