Abstract
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.
Highlights
We report how zebrafish-based screening of marine natural product (MNP) extracts for novel compounds with the potential to treat epilepsy led to the discovery of the pronounced antiseizure activity of plinabulin, a known drug candidate that is in clinical trials for other therapeutic indications (i.e., the treatment of non-small cell lung cancer (NSCLC) in combination with docetaxel, as well as for the prevention of chemotherapy-induced neutropenia (CIN)) [9,10,11,12,13,14]
We report the antiseizure activity of halimide and plinabulin in the zebrafish pentylenetetrazole (PTZ) seizure model, a well-known standard model used for drug discovery within PharmaSea, as well as the characterization of plinabulin’s activity against drug-resistant seizures in both the recently developed larval zebrafish ethyl ketopentenoate (EKP) seizure model [27] and the well-known mouse
The photomotor response (PMR) is a stereotypical behavior of 30–40 h post-fertilization zebrafish embryos that is triggered by two subsequent high-intensity light pulses and is used for high-throughput neuroactive drug discovery because of its robustness and behavioral fingerprinting utility [30,31,32]
Summary
The search for new microbial diversity by PharmaSea included extreme marine environments, such as deep ocean trenches and cold and hot vent habitats [1]. This systematic search led to the discovery of many novel molecules and the improved understanding of the therapeutic potential of new and already known small molecules (selected references [2,3,5,6,7,8]). We report how zebrafish-based screening of marine natural product (MNP) extracts for novel compounds with the potential to treat epilepsy led to the discovery of the pronounced antiseizure activity of plinabulin, a known drug candidate that is in clinical trials for other therapeutic indications (i.e., the treatment of non-small cell lung cancer (NSCLC) in combination with docetaxel, as well as for the prevention of chemotherapy-induced neutropenia (CIN)) [9,10,11,12,13,14]
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