Methionine Sulfoximine as a Tool for Studying Temporal Lobe Epilepsy: Initiator, Developer, Attenuator

Methionine sulfoximine (MSO) is a compound originally discovered as a byproduct of agene-based milled flour maturation. MSO irreversibly inhibits the astrocytic enzyme glutamine synthase (GS) but also interferes with the transport of glutamine (Gln) and of glutamate (Glu), and γ-aminobutyric acid (GABA) synthesized within the Glu/Gln-GABA cycle, in this way dysregulating neurotransmission balance in favor of excitation. No wonder that intraperitoneal administration of MSO has long been known to induce behavioral and/or electrographic seizures. Recently, a temporal lobe epilepsy (TLE) model based on local continuous infusion of MSO into the hippocampus has been developed reproducing the main features of human mesial TLE: induction of focal seizures, their spreading, increase in intensity over time, and development of spontaneous recurrent seizures. Fully developed TLE in this model is associated with hippocampal degeneration, hallmarked by reactive astrogliosis, and causally related to the concomitant loss of GS-containing astrocytes. By contrast, short-term pre-exposure of rats to relatively low MSO doses that only moderately inhibited GS, attenuated and delayed the initial seizures in the lithium-pilocarpine model of TLE and in other seizure-associated contexts: in the pentylenetetrazole kindling model in rat, and in spontaneously firing or electrically stimulated brain slices. The anti-initial seizure activity of MSO may partly bypass inhibition of GS: the postulated mechanisms include: (i) decreased release of excitatory neurotransmitter Glu, (ii) prevention or diminution of seizure-associated brain edema, (iii) stimulation of glycogenesis, an energy-sparing process; (iv) central or peripheral hypothermia. Further work is needed to verify either of the above mechanisms.