DNA topoisomerase I inhibitors ameliorate seizure-like behaviors and paralysis in a Drosophila model of epilepsy.
The Drosophila DNA topoisomerase type I mutant allele, top1JS is an effective general seizure-suppressor mutation, reverting seizure-sensitive phenotypes of several mutant strains in a genetic model of epilepsy. Seizure-suppression is caused by reduced transcription of the top1 (topoisomerase I gene) gene [Song J, Hu J, Tanouye MA. (2007) Seizure suppression by top1 mutations in Drosophila. J Neurosci 27(11):2927-2937]. Here, we examine the possibility that pharmaceutical inhibition of Top1 (topoisomerase I protein) enzymatic activity may also be effective at reducing seizure phenotypes. We investigate the effect of vertebrate Top1 inhibitor camptothecin (CPT) along with two related compounds, apigenin and kaempferol, when fed to seizure-sensitive mutant Drosophila. All three Top1 inhibitors were found to suppress phenotypes in these mutants. In particular, for drug treatments, the recovery time from seizure and paralysis is greatly reduced compared with untreated animals. Intriguingly we find that chronic drug treatments result in a small reduction in seizure sensitivity. Taken together, the results suggest that Top1 inhibitors may have the potential to be developed into effective anti-epileptic drugs, especially for brain tumor patients presenting with epilepsy.
Song
J
J
Department of Environmental Sciences, Policy and Management, Division of Organisms and Environment, University of California, Berkeley, Berkeley, CA 94720, USA.
Parker
L
L
Hormozi
L
L
Tanouye
M A
MA
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001959:Bromates / Q000494:pharmacology / Q000627:therapeutic use; D002166:Camptothecin / Q000627:therapeutic use*; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D004334:Drug Administration Schedule; D004558:Electric Stimulation / Q000379:methods; D004597:Electroshock / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004827:Epilepsy / Q000150:complications / Q000209:etiology / Q000235:genetics; D005071:Evoked Potentials / Q000187:drug effects / Q000528:radiation effects; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018482:Muscle, Skeletal / Q000473:pathology / Q000528:radiation effects; D009154:Mutation / Q000235:genetics; D010243:Paralysis / Q000188:drug therapy* / Q000209:etiology; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D059004:Topoisomerase I Inhibitors; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D001959:Bromates; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C019536:potassium bromate; D014635:Valproic Acid; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin