Abstracts

Rationale: Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of drug-resistant, localization-related epilepsies in humans.  One potential therapeutic target is astrocytic glutamine synthetase (GS), the enzyme that metabolizes glutamate to glutamine, as this enzyme has been shown to be deficient in epileptogenic foci (Lancet 2004; 363: 28-37). Loss of GS can be modeled by infusing the GS inhibitor methionine sulfoximine (MSO) into the entorhinal-hippocampal area in rats.  Preliminary data from our lab indicates that glutamine is deficient in the hippocampus of this model. Here, we asked whether oral supplementation with glutamine would affect epileptogenesis in the MSO model.  The parameters of epileptogenesis assessed were seizure frequency and severity over a 3-week period. Methods: Male Sprague Dawley rats were given a diet of either glutamine (n=8) or water (n=8) for a period of 10 days.  Following this period, both groups of rats were implanted with an osmotic pump continuously infusing MSO into the entorhinal cortex. Screw electrodes were placed above neocortex and following surgery EEG was measured continuously for 21 days.  The EEG was correlated with simultaneous video recordings to determine the stage of seizures according to a modified Racine scale. Results: When looking at total seizure frequency, glutamine treated rats showed a significantly higher number of seizures during the first three days (early) following surgery (p<0.01), but not during days 4-21 (late), when compared to the water control group.  When looking at total convulsive seizures, glutamine treated rats showed a significantly higher number of seizures during the first three days following surgery (p<0.0001), but not during days 4-21, when compared to the water control group.  There was a decrease in the number of convulsive seizures in the glutamine treated animals and an increase in the water treated animals between the early and late time-periods (p<0.05). There was no difference between glutamine and water treated groups with respect to total non-convulsive seizures during any time period. Conclusions: Glutamine markedly elevates the number of severe seizures early after astrocytic GS inhibition, but has no effect on frequency or severity of seizures after the initial insult. Furthermore, glutamine has no effect on the frequency of non-convulsive seizures.  These findings are significant because they help to elucidate the role of the components of the glutamine-glutamate-GABA metabolic pathway on the development of seizure severity and epileptogenesis.   Funding: NINDS K08 NS058674, R01 NS070824, and NCATS UL1 RR024139