Abstract
There is a high need for the development of new and improved antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening of MNPs. To this end, the embryonic zebrafish photomotor response assay and the larval zebrafish pentylenetetrazole (PTZ) model were used to screen MNP extracts for neuroactivity and antiseizure activity, respectively. Here we report the identification of the two known isoquinoline alkaloids TMC-120A and TMC-120B as novel antiseizure compounds, which were isolated by bioactivity-guided purification from the marine-derived fungus Aspergillus insuetus. TMC-120A and TMC-120B were observed to significantly lower PTZ-induced seizures and epileptiform brain activity in the larval zebrafish PTZ seizure model. In addition, their structural analogues TMC-120C, penicisochroman G, and ustusorane B were isolated and also significantly lowered PTZ-induced seizures. Finally, TMC-120A and TMC-120B were investigated in a mouse model of drug-resistant focal seizures. Compound treatment significantly shortened the seizure duration, thereby confirming their antiseizure activity. These data underscore the possibility to translate findings in zebrafish to mice in the field of epilepsy and the potential of the marine environment for ASD discovery.
Highlights
Marine drug discovery has only been systematically performed since the 1970s, once scuba diving could be used routinely [1]
In this study we report the successful use of our zebrafish-based screening approach to identify the two known isoquinoline alkaloids TMC-120A
To confirm that TMC-120A and TMC-120B, isolated from the most bioactive fractions, are the active constituents, their antiseizure activity was investigated in the zebrafish PTZ seizure model (Figure 6A–D)
Summary
Marine drug discovery has only been systematically performed since the 1970s, once scuba diving could be used routinely [1]. Zebrafish capture much of the complexity of vertebrate physiology including the central nervous system, and can be used for phenotype-based drug discovery which allows the identification of bioactive compounds independently of their mode of action [24,25] For these reasons, we used embryonic and larval zebrafish bioassays as an initial screening platform to identify MNPs with antiseizure activity prior to further validation and characterization in rodent seizure models. Drugs 2019, 17, x in the North Sea, in between Denmark and Norway This led to the isolation of the structural proposed as potential ASD leads that are worth further investigation for the treatment of epileptic analogues TMC-120C, penicisochroman G, and ustusorane B. Potential ASD leads that are worth further investigation for the treatment of epileptic seizures
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