Pretreatment with a glutamine synthetase inhibitor MSO delays the onset of initial seizures induced by pilocarpine in juvenile rats

Inhibition of Glutamate Release, but Not of Glutamine Recycling to Glutamate, Is Involved in Delaying the Onset of Initial Lithium-Pilocarpine-Induced Seizures in Young Rats by a Non-Convulsive MSO Dose

“…MSO significantly reduced behavioral symptoms of seizures throughout the whole 60-min observation period ( Figure 1 A) as well as during the short 15-min period ( Figure 1 D), the magnitude similar to that observed previously [ 29 ]. MSO significantly delayed the onset of generalized seizure in the “short period” group ( Figure 1 E,F) and tended to delay the onset in the “long period” group ( Figure 1 B,C), again, in a manner similar to that previously described [ 29 ]. As shown in the heat map ( Figure 1 G), the severity of seizures between individuals varied substantially throughout whole observation period.…”

“…We recently have demonstrated that in 24-day rats treated with lithium-pilocarpine (Li-Pilo) following exactly the procedure described in [ 26 ], pretreatment with MSO at a low dose (75 mg/kg b.w.) which produced no convulsions, delayed the onset of and attenuated the initial convulsive and electrographic seizures [ 29 ]. It appeared reasonable to speculate that MSO at this low dose inhibited an aspect of glutamatergic transmission critical for provoking the initial seizures.…”

Selected Molecular Targets for Antiepileptogenesis

“…We attempted to evaluate the so-far never analyzed relation of c-Fos expression to two characteristics of initial seizures: (i) the time lapse between the stimulus application and the onset of the first seizure and (ii) seizure intensity as measured with the Racine score. In this laboratory, each of the two parameters and their correlation with glutamatergic transmission were investigated in the lithium-pilocarpine model in young rats, until 60 min after the stimulus application in a minute timescale [ 68 ]. The study revealed considerable animal-to-animal variations with regards to parameters (i) and (ii).…”

“…While the above observations strongly support the status of c-Fos as an early, seizure duration-related marker of epileptogenesis, they leave open the question of the contribution of c-Fos to epileptogenesis and, thus, of its assignment to the list of therapeutic targets. Since c-Fos positively regulates several aspects of neural plasticity [ 68 ], its activation in the initial stages of epileptogenesis may be considered as a neuroprotective response. Some experimental data appear to support this view.…”

“…A correlation coefficient was considered statistically significant at the two‒tailed p ‒value <0.05. For a more detailed description of the model used, see Reference [ 68 ]. The total RNA was isolated from the hippocampus using a TRI reagent (Sigma).…”