A neurochemical study of the novel antiepileptic drug retigabine in mouse brain.
The novel antiepileptic drug, retigabine, has been reported to have multiple mechanisms of action, including potentiation of gamma -aminobutyric acid (GABA) and glutamate synthesis. We have investigated its effects on several GABA- and glutamate-related neurochemical parameters in mouse brain. Mice were administered retigabine either as a single dose or daily for 5 days. At 4 h after dosing, brains were removed and analysed for GABA, glutamate, and glutamine concentrations and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single doses of retigabine significantly lowered brain concentrations of glutamate and glutamine. Repeated treatment significantly reduced the activity of GABA-transaminase. The drug was essentially without effect on all other parameters investigated. These results suggest that retigabine blocks GABA metabolism rather than enhancing GABA synthesis. In addition, the drug may also lower brain concentrations of the excitatory neurotransmitter glutamate and its precursor, glutamine. These effects may contribute to the antiepileptic action of retigabine.
Sills
G J
GJ
Epilepsy Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland. g.j.sills@clinmed.gla.ac.uk
Rundfeldt
C
C
Butler
E
E
Forrest
G
G
Thompson
G G
GG
Brodie
M J
MJ
D000612:4-Aminobutyrate Transaminase / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000032:analysis; D005973:Glutamine / Q000032:analysis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010655:Phenylenediamines / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000378:metabolism
D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; D005973:Glutamine; C101866:ezogabine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D005968:Glutamate Decarboxylase