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

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 r...

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Bibliographic Details
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
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Summary: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.
ISSN:0885-7490
1573-7365
DOI:10.1023/A:1020737125843