Abstracts

Glutamine synthetase (GS), which converts glutamate to glutamine, is deficient in specific areas of the sclerotic hippocampus in patients with mesial temporal lobe epilepsy (MTLE). A key question is whether hippocampal GS deficiency is causally related to the generation of seizures in MTLE., The GS inhibitor methionine sulfoximine (MSO) was infused chronically into the hippocampus of rats at the following doses: 1.0 mg/ml (n=4), 2.5 mg/ml (n=18), 5.0 mg/ml (n=11), and 10 mg/ml (n=39). Saline infused animals (n=30) were used as controls. The animals underwent long-term intracranial EEG and video monitoring for up to 83 days; the activity of GS was assessed biochemically; and the brain pathology was explored by Nissl- and silver-staining of histological sections., Infusion of MSO, but not saline, caused significant (p[lt]0.01) inhibition of brain glutamine synthetase. A dose of [ge] 2.5 mg/ml MSO consistently produced spontaneously recurrent seizures (stages I [ndash] IV) after a clinically silent interval of 5-9 days, whereas no seizures were observed in saline treated animals. Hippocampal gliosis and neurodegeneration were present in all MSO-treated animals in a dose-dependant manner (i.e. increasing severity in pathology change with higher dose of MSO)., These studies suggest that the deficiency of hippocampal GS is a causative factor in the generation of spontaneously recurring seizures in MTLE, and that GS may represent a novel therapeutic target for this disease.,