TY - THES ID - 136195846 TI - Plinabulin, a lead compound for drug-resistant epilepsy: efficacy and mode-of-action investigation AU - Roux, Emma AU - de Witte, Peter AU - Copmans, Daniëlle AU - KU Leuven. Faculteit Farmaceutische Wetenschappen. Opleiding Master in de geneesmiddelenontwikkeling (nieuw programma vanaf 2017-2018) (Leuven) PY - 2020 PB - Leuven KU Leuven. Faculteit Farmaceutische Wetenschappen DB - UniCat UR - https://www.unicat.be/uniCat?func=search&query=sysid:136195846 AB - Epilepsy is one of the most common neurological diseases, affecting more than 70 million people worldwide, and is characterized by an enduring predisposition to experience unprovoked seizures. The current anti-epileptic treatment strategy is based on pharmacotherapy with antiseizure drugs (ASDs) to control seizures. However, despite many efforts, 30% of epilepsy patients suffer from a drug-resistant form of epilepsy. Hence, there is a high unmet medical need to develop ASDs that are effective for drug-resistant seizures. Recently, the Laboratory for Molecular Biodiscovery identified a novel antiseizure compound, i.e., plinabulin, using a zebrafish-based screening approach that relied on the larval zebrafish pentylenetetrazole (PTZ) seizure model. Plinabulin showed an additional promising antiseizure efficacy against drug-resistant seizures in both the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6-Hz psychomotor seizure model. Interestingly, plinabulin is a well-known microtubule depolymerizing agent (MDA) that is currently in late-stage clinical trials for different therapeutic indications in the field of cancer. The initial characterization of plinabulin’s antiseizure efficacy was performed after a short-term treatment period. As plinabulin has a limited water solubility that could limit the amounts of compound that reach the zebrafish brain, this study aimed to further characterize the antiseizure efficacy in the larval zebrafish PTZ and EKP seizure models by investigating whether the efficacy could be improved by prolonging the treatment period and by determining how the efficacy compares to that of clinically used ASDs. Moreover, this project aimed to explore whether plinabulin’s known mechanism of action (MOA) in the field of cancer could also be responsible for its antiseizure action by investigating if functional analogues of plinabulin (i.e., colchicine and indibulin) also exhibit antiseizure activity in the larval zebrafish EKP seizure model. Plinabulin’s antiseizure efficacy in the larval zebrafish PTZ and EKP seizure models increased remarkably by prolonging the treatment period. In comparison to the positive control of each seizure model, plinabulin was observed to be at least as effective as perampanel, and even more effective than sodium valproate, which are both clinically used ASDs. These data show that plinabulin has a promising antiseizure efficacy in the zebrafish model and further research is needed to investigate plinabulin’s antiseizure potential in rodent seizure models. Finally, no antiseizure properties were observed for colchicine and indibulin in the zebrafish EKP seizure model. These data suggest that microtubule depolymerization, if involved in the antiseizure activity of plinabulin, is at least not sufficient for an antiseizure activity. Further research is needed to identify the antiseizure target(s) of plinabulin and to understand its MOA. ER -