PharmaSea performed large-scale in vivo screening of marine
natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat
epilepsy. In this study, we report the discovery of two new antiseizure compounds, the
2,5-diketopiperazine halimide and its semi-synthetic analogue,
plinabulin. Interestingly, these are both known microtubule destabilizing agents, and
plinabulin could have the potential for
drug repurposing, as it is already in clinical trials for the prevention of
chemotherapy-induced
neutropenia and treatment of
non-small cell lung cancer. Both halimide and
plinabulin were found to have antiseizure activity in the larval zebrafish
pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of
plinabulin was further characterized in animal models of
drug-resistant
seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model.
Plinabulin was observed to be highly effective against EKP-induced
seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that
plinabulin could be of interest for the treatment of
drug-resistant
seizures. Finally, the investigation of two functional analogues,
colchicine and
indibulin, which were observed to be inactive against EKP-induced
seizures, suggests that microtubule depolymerization does not underpin
plinabulin's antiseizure action.