The Effects of Pyridoxine Antagonists and Other Convulsive Agents on Amino Acid Concentrations of the Mouse Brain*

Abstract

A SEIZURE state has been produced by pyridoxine deprivation in lower mammals and man (HUNT er al., 1954; COURSIN, 1954). These seizures are believed to result from an inhibition of the enzymic processes of the brain in which pyridoxine functions as a co-enzyme (ROBERTS er al., 1958~) and which act mainly to metabolize glutamic acid through the decarboxylation of glutamic acid to y-aminobutyric acid (GABA) and the transamination of glutamic acid with other a-amino acids. The relationship of the metabolic defects induced by this enzymic inhibition to the evoked seizures is, however, not known.GAMMON et a/. (1960) used 4-methoxymethylpyridoxine (MOB6), a specific pyridoxine antagonist, to produce seizures in mice through acute pyridoxine deficiency. They found that seizures caused by MOB6 could be prevented by prior treatment of the animals with pyridoxine or GABA. The present investigation was undertaken to elucidate the amino acid changes which occur during both the seizure state produced by pyridoxine deficiency and the prevention of this state by protecting agents. In addition, several other convulsive agents were studied to determine if their effect on amino acid metabolism might parallel that seen during the seizure state induced by pyridoxine deficiency. MATERIALS A N D M E T H O D SMale Swiss white mice weighing 20g were tested in nine experimental situations as follows. Control series. At least 6 normal control animals were sacrificed during each experimental period.Pyridoxine series. Pyridoxine hydrochloride in a dose of 1.8 mg per mouse was administered to 18 animals, and the animals were sacrificed 1 hr later.y-Aminobutyric acidseries. GABA in a dose of 100 mgper mouse was administered to 18 animals, and the animals were sacrificed 1 hr later. 4-Merhoxymethylpyridoxine series. MOB6was administered in a dose of 0 . 6~ per mouse, the convulsant dose 100 (CDIo0), in I6 animals and 1.2 mg per mouse, twice the CDIpo, in 5 animals.The animals were sacrificed during a seizure.Pyridoxine-MOB6 series. Pyridoxine hydrochloride was administered in a dose of 1.8 mg per mouse in 18 animals followed in 15 min by administration of 0.6 mg of MOB6 per mouse, The animals were sacrificed 45 rnin after MOB6 administration.GAEA-MOB6 series. GABA in a dose of 100mg per mouse was administered to 18 mice followed in i S min by administration of 0.8 mg of MOB6 per mouse. Animals were sacrificed while in seizure. Each of a second group of 12 mice was injected with 100 mg of GABA followed in 15 min by 0.6 mg of MOB6. These animals did not convulse and were sacrificed 45 min after the MOB6 administration.This paper was awarded second prize in the contest sponsored by The Neurosurgical Foundation t Present address: Presbyterian Hospital, Philadelphia 4, Pa. I 219 220 ROBERT P. KAMRIN and ANNE A. KAMWN Penfumefhyleriefefruzol (Mefruzol) series. Pentamethylenetetrazol in a dose of 6 mg per mouse, twice the lethal dose 100 (LD,,,) (CHEN and BOHNER. 1958). was administered to 19 animals which were sacrificed while in seizure. Pierofoxin...

The Excitation and Depression of Mammalian Cortical Neurones by Amino Acids

“…It is pertinent to point out that a related substance, y-butyrolactone, which also has central depressant effects (Giarman & Schmidt, 1963) does not increase the brain level of GABA. However total brain levels of GABA may not necessarily be related to the state of excitability of central neurones (see also Kamrin & Kamrin, 1961;Medina, 1963) and it may be more relevant to these studies to ascertain differences in the distribution of amino acids between intra-and extra-cellular compartments (see Curtis & Watkins, 1960a).…”

Biochemical Pharmacology of GABA in CNS

“…(1960), Kamrin and Kamrin (1961) Chen et at. (1972) fj-N-Oxalyl-L-,Ot,fj-diamino-250 Young rat Cheema et at.…”