GABA-Transaminase antisense oligodeoxynucleotide modulates cocaine- and pentylenetetrazol-induced seizures in mice

• Published in: Metabolic brain disease 1999-12, Vol.14 (4), p.253-263
• Main Authors: ABEL, M. S, KOHLI, N
• Format: Article
• Language: English
• Subjects: 4-Aminobutyrate Transaminase - drug effects; 4-Aminobutyrate Transaminase - genetics; 4-Aminobutyrate Transaminase - metabolism; Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Cerebral Ventricles - cytology; Cerebral Ventricles - drug effects; Cerebral Ventricles - metabolism; Cocaine - pharmacology; Convulsants - pharmacology; Dopamine Uptake Inhibitors - pharmacology; Dose-Response Relationship, Drug; Epilepsy - drug therapy; Epilepsy - physiopathology; gamma-Aminobutyric Acid - metabolism; Injections - methods; Male; Medical sciences; Mice; Mice, Inbred BALB C; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuropharmacology; Oligodeoxyribonucleotides, Antisense - pharmacology; Pentylenetetrazole - pharmacology; Pharmacology. Drug treatments; Seizures - chemically induced; Seizures - drug therapy; Seizures - physiopathology; Time Factors
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1023/A:1020737125843

The mechanism of action of many anticonvulsive agents is to increase the function of the GABAergic system. Inhibition of GABA-Transaminase (GABA-T), the degradative enzyme for GABA, increases GABA levels in the brain. In this study, antisense oligodeoxynucleotides (ASO) targeted at the start codon region of GABA-Transaminase mRNA were used to modify seizure activity. Mice were treated, by intracerebroventricular injection, with antisense oligos or appropriate controls. At various times after treatment, the animals were challenged with cocaine (70 mg/kg, i.p.) and observed for seizure activity. At 15 hours after treatment, 1.152 and 1.44 nmol antisense oligo blocked cocaine-induced seizures. There was no effect of antisense oligo 8 or 36 hours after treatment. In addition, treatment with 7.2 nmol antisense oligo prevented pentylenetetrazol-induced seizures. These data demonstrate the modulation of seizure threshold using antisense oligodeoxynucleotides to GABA-T.