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 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.
Abel
M S
MS
Department of Cell Biology and Anatomy FUHS/The Chicago Medical School, North Chicago, IL 60064, USA. abelm@finchcms.edu
Kohli
N
N
D000612:4-Aminobutyrate Transaminase / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002552:Cerebral Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology; D007267:Injections / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D010433:Pentylenetetrazole / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D003292:Convulsants; D018765:Dopamine Uptake Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D003042:Cocaine; D010433:Pentylenetetrazole