title: Effects of 4-methylimidazole on cerebral glutamate decarboxylase activity and specific GABA receptor binding in mice.
abstract: 4-methylimidazole (4MeI) is a tremorogenic and convulsive agent of concern both in human and veterinary toxicology. The in vitro effects of 4MeI (5 microM-20 mM) on cerebral glutamate decarboxylase (GAD) activity and (in concentrations up to 50 mM) on binding of [(3)H]GABA to cerebral GABA receptors were tested in brain tissue from B6D2 mice. The effects of 1-methylimidazole (1MeI), 2-methylimidazole (2MeI), 4-methylhydroxy-imidazole (4MeOHI), imidazole-4-acetic acid (4AcI) (all in concentrations of 5-20 mM) and imidazole (20 mM) on GAD activity were also tested. In addition, the effect of a lethal dose of 4MeI (250 mg/kg ip) to B6D2 mice in vivo on the postmortem concentrations of gamma-aminobutyric acid (GABA) and glutamate in their brains were measured. In all experiments, student's t-test was used for statistical comparison. 4MeI in concentrations of 2 mM and above did inhibit GAD activity significantly in vitro, but glutamate and GABA concentrations in mouse brains after lethal 4MeI poisoning were not significantly different from control values. The effect of 2MeI on GAD activity was stronger than the effect of 4MeI. Binding of [(3)H]GABA to cerebral GABA receptors in vitro was significantly inhibited only at 4MeI concentrations of 5 mM and above. The results indicate that neither inhibition of GABA synthesis nor competitive inhibition of the binding of GABA to its receptors are likely mechanisms for the excitation and convulsions seen in 4MeI poisoning in animals.
authors.affiliation: Department of Production Animal Clinical Sciences, Norwegian School of Veterinary Science, Oslo, Norway. tore.sivertsen@veths.no
authors.forename: Tore
authors.initials: T
authors.lastname: Sivertsen
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Nygaard
authors.forename: Gro
authors.initials: G
authors.lastname: Mathisen
authors.forename: Frode
authors.initials: F
authors.lastname: Fonnum
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C023439:4-methylimidazole