Modulation of planarian seizure-like activity via antiseizure medications

Abstract

Acute chemical exposure to organophosphorus compounds (OPs) arising from terrorist attacks or accidental poisonings pose a serious threat to human health. Acetylcholinesterase inhibition due to acute OP exposure causes a cholinergic crisis, manifested as increased secretions, respiratory distress, loss of consciousness, seizures, and ultimately death if left untreated. Benzodiazepines, such as midazolam, are currently used to stop OP-induced seizures, but must be administered within minutes after exposure to be effective. This makes midazolam impractical for large-scale civilian emergencies. Thus, there is a need to identify novel antiseizure medications (ASMs) that are equally effective even when administered later. It has been challenging to identify such compounds with traditional mammalian testing; high throughput screening assays that can quickly and cost-effectively evaluate many candidates for their potential as an ASM are needed. Planarians are aquatic invertebrates that are suitable organismal models for OP neurotoxicity studies due to the conservation of OP targets and their ability to metabolize OPs. Here, we built on our prior work that introduced a computational image analysis pipeline to quantify planarian seizure-like activity (pSLA) in two planarian species (Dugesia japonica and Girardia dorotocephala). We previously used this approach to characterize pSLA following acute exposure (up to 30 minutes) to seizurogenic compounds. In the present study, we asked whether pSLA induced by the OP pesticide parathion, pentylenetetrazole, or NMDA could be rescued by co-exposure to four ASMs: midazolam, topiramate, MK-801, and carbamazepine. All tested ASMs were effective at reducing parathion-induced pSLA in one planarian species. However, ASM responses varied substantially across proconvulsants and planarian species. Defining the molecular mechanisms underlying pSLA will be essential for establishing planarians as a reliable model for ASM discovery.