DNA topoisomerase I inhibitors ameliorate seizure-like behaviors and paralysis in a Drosophila model of epilepsy

Abstract

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.

Figure 1. DLM motor neuron function during GF-evoked response failure

An example of the DLM recordings before and after ECS stimulation (buzz). Drug-treated flies have shorter synaptic failure duration time than untreated flies: control bss¹ flies have an average synaptic failure duration time of 104 s; while CPT-treated bss¹ flies have an average synaptic failure duration time of 74s (p<0.007; Student's t-test). Following a buzz, GF stimulation was resumed to test for the failure and then recovery of evoked muscle potentials. Recovery from failure is defined here by two successive GF test stimuli giving rise to normal latency responses (Tanouye and Wyman, 1980; Pavlidis and Tanouye, 1995). Calibration: 20 mV, 2 ms. n ≥ 10 for electrophysiology.