Glutamate decarboxylase (EC 4.1.1.15, GAD) activity was studied in the brain of 12-day-old and adult rats treated with 3-mercaptopropionic acid (3-MPA), an inhibitor of GAD competitive with glutamate. Control GAD activity in the brains of immature animals (91.8 +/- 18.2 nmol/h/mg of protein) was lower than that of the adult rats (228 +/- 37.5 nmol/h/mg of protein). Brain GAD inhibition in adult rats was 58% at the onset of seizures (9 min on the average after administration of 70 mg 3-MPA/kg). At the same time, 3-MPA-treated young rats exhibited 76% inhibition of GAD despite the fact that at 9 min these animals were not yet having seizures. At the onset of seizures (19 min after 3-MPA on the average) their GAD activity remained at the same level. The difference between the groups was not related to the presence of the coenzyme pyridoxal-5'-phosphate in the enzyme assay. The inhibition of GAD by 3-MPA in vitro in the immature and adult brains was similar (Ki at 5.1 microM and 4.8 microM concentrations of 3-MPA, respectively). Identical values were found for Km of GAD (at 4.5 mM concentration of L-glutamate). Calculations based on the results suggest that 3-MPA enters the immature brain more easily than the brain of the adult animals. While GAD inhibition by 3-MPA is the primary cause of seizures, their onset is influenced by other factors, in which the immature brain differs from the adult one and which may include less sensitivity to GABA decrease due to relative overactivity of the GABA system.

Department of Biochemical Sciences Faculty of Pharmacy Charles University Hradec Králové Prague Czech Republic

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