Glutamic Acid and Glutamine Metabolism in Cerebral Cortex After Seizures Induced by Methionine Sulphoximine

Abstract

M-NINEsulphoximine is the toxic principle isolated from flour treated by the nitrogen trichloride, or 'Agne'. process (BENTLEY er al., MELUNBY, 1946 MELUNBY, , 1947 MWM and REINER, 1950). It is a potent convukant for all mammalian species testad, producing a semi-chronic seizure state within 12 to 24 hours after oral or puenteml administration (REINER et ai., 1950; TOWER, 1958~). It has also been shown to inhibit the growth of various microorganisms and to be counteracted in this respect by addition of methionine or glutamine to the culture media (HEATHCOTE and PACE, 1950; NEWEU and CARMAN, 1950). Inhibition of cerebral glutamine synthesis by methionine sulphoximine (PACE and MCDERMOTT, 1952) appears to be closely analogous to similar inhibition by methionhe sulphoxide in a variety of tissue preparations (BOREK et al., 1W; ELLIOTT and GALE, 1948; SPECK, 1949). The seizures ~induccd by methionine sulphoximine can be prevented or arrested by in vim sdministration of large doses of methionine, glutamine, or asparagine (RErNeR et a/., 1950; TOWER, 19596). Cerebral cortex slices from cats with such seizures exhibit during incubation in uirro a failure of 'bound' acetylcholine production, which can be corrected by in oitro addition of methionine, glutamine, or asparagine (TOWER, 19596; TOWER and ELLIOIT, 1953). These various observations suggest that methionine sulphoximine acts both as a methionine antagonist or antimetabolite and as an inhibitor of glutamine metabolism. It is not apparent whether or not the two effects ICC directly interrelated, nor is the exact mode of action of methionine sulphoximine ckp1. The studies reported here on metabolism of glutamic acid and glutamine in incubated slices of cat cerebral cortex were undertaken to obtain further information on thcsc points, since disturbances of glutamic acid metabolism appear to be common to many different seizure states (TOWFR, 19596). Some preliminary accounts have beca previously reported (TOWER, 19576; 19596). MATERIALS A N D METHODS AU studies wcrc carried out on stock, adult cats. DL-methionine sulphoximine was generously supplpd by the late Dr. L. REINITI of Wallaa and Tiernan Co.. Inc., Bclleville. New Jersey. Reagent grdc L -~~~I K I acid8obtaincd from Nutritiwal Biochemicals Corp., Ckveland, Ohio, and a&&mhu? Iripbo6phatc sodium (ATP) from S i p Chemical Co., St. Louis, Missouri. Analytically prre 2p)1Tdidiaonc and pyridoxal phosphate w e r~ kindly donated by Dr. L. S m of Mercksbsrpc and Dohmc Rcsarch Lsboraton'es, Rabway. New Jersey. All other chemicals were of w t p i c . obtaiad from usual commercial sources. ycre i n d d in cats by htrapcritoncal injection of 0.1 m-moles (IS-U)mg/kg body mya,dmahionint sulphoximine diaolvcd in 2 ml of0.9% NaCl solution. With this dose seizures 80

Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal

“…(3) Impairment of mitochondrial function by Gln at moderate levels of HE could have sensitized the brain to MSO, effects independent of its inhibition of GS. Moreover, MSO is a convulsing agent frequently used to model epileptic discharges in animals [61], which at the cellular level is associated with increased glycogen synthesis in astrocytes [62], a reaction also directly evoked by astrocytic swelling [63]. As judged from studies in in vitro systems, MSO inhibits Gln uptake in one or more CNS cell types in brain slices [64], and induces a massive Gln efflux from astrocytes [42].…”

Epilepsy, Regulation of Brain Energy Metabolism and Neurotransmission

“…MSO strongly resembles glutamate, and it has been suggested that it can induce seizures by mimicking the effect of this excitatory amino-acid [165, 166]. Indeed, if MSO can replace glutamate in the synaptic cleft, it could stimulate neurotransmission and therefore induce seizures, but this mechanism of action is still not clearly understood.…”

Selection of two lines of mice based on latency to onset of methionine sulfoximine seizures

“…The hypothesis of MSO action through glutamatergic neurotransmission, however, is not in agreement with changes in glutamate content after MSO administration. Indeed, paradoxically, no increase in brain glutamate content has been reported after administration of a convulsive dose of MSO (Engelsen & Fonnum, 1985; Fonnum and Paulsen 1990; Somers & Beckstead, 1990), even if the latter convulsant is a powerful and irreversible inhibitor of glutamine synthetase (Peters & Tower, 1959; Meister, 1978; Blin et al., 2002). Nevertheless, according to our present data we can suggest that MSO could act rather directly on glutamatergic receptors or glutamate transporters, that is, on glutamatergic pathways using mechanisms yet to be determined.…”

“…The supposed effect of MSO through glutamate neurotransmission because of the resemblance between the two preceding molecules (Peters & Tower, 1959; Meister, 1978) was not experimentally supported (Engelsen & Fonnum, 1985; Fonnum and Paulsen 1990; Somers & Beckstead, 1990; Blin et al., 2002). Therefore, the precise mechanism of MSO‐dependent convulsions is not clearly understood and remains to be elucidated.…”