Abstracts

Rationale: MTLE is one of the most common forms of drug-resistant, focal epilepsies in humans. More efficacious treatments for this disease are therefore necessary. However, the discovery of better treatments has been lagging, partly due to a lack of in vivo models that replicate key features of human MTLE. We recently developed an improved model of MTLE by chronic infusion of MSO unilaterally into the hippocampus of rats (Brain, 2008; 131:2061-2070). This paradigm results in inhibition of glutamine synthetase in the hippocampus and development of chronic temporal lobe seizures. Both of these features are hallmarks of human MTLE (Lancet, 2004; 363:28-37). 5-AV has been suggested to modulate the glutamine-glutamate-GABA metabolic pathway (J Neurochem, 1983; 40:1063-1068), which is perturbed in MTLE. Thus, we hypothesized that 5-AV would alter the expression of seizures in the MSO model of MTLE.Methods: Male Sprague Dawley rats weighing between 300-330 g were implanted with an Alzet pump placed subcutaneously in the abdominal region, releasing either 5-AV (n=4) or phosphate buffered saline (PBS, n=2) at a rate of 2.5 l/hr over 28 days. Five to 7 days after surgery, all rats were implanted with an intracranial pump injecting MSO into the dentate granule cells of the hippocampus in the right hemisphere at a rate of 0.25 l/hr. Following the second surgery, intracranial EEG was measured from the left and right hemispheres above the anterior hippocampal area for a continuous period of 21 days. EEG analysis was correlated with simultaneous video recordings to determine the stage of seizure according to the Racine scale. Results: 5-AV-treated rats experienced a significantly lower number of seizures (~2 seizures/day) than PBS-treated rats (~6 seizures/day) during the first 3 days following MSO pump placement (p<0.01). Both groups showed similar seizure frequency over days 4-21 (~2 seizures/day). While percent time spent in stage 4 and 5 seizures remained constant in 5-AV treated rats over days (10%), it significantly increased in the PBS-treated rats (~80%), as demonstrated by a repeated measures ANOVA. There was a significant effect of treatment (p=0.026), a significant effect of days (p<0.0001), and a significant treatment by days interaction (p<0.0001). Post Hoc Neuman Kuels indicated that 5-AV treated rats showed a significantly lower percent of stage 4 and 5 seizures than PBS-treated rats during the 2nd and 3rd week of MSO treatment (p<0.05).Conclusions: 5-AV markedly reduces the number of seizures initially and suppresses the development of stage 4 and 5 seizures in the MSO rat model of epilepsy. These results may have implications for the therapeutic use of 5-AV or related compounds in treating mesial temporal lobe seizures and for our understanding of the mechanism of spontaneous seizures in MTLE.