ZEBRAFISH-BASED IDENTIFICATION OF APICULAREN A AS AN ANTICONVULSANT COMPOUND FROM MYXOBACTERIA

Purpose: Given the need for new and improved anti-epileptic drugs, this study focused on the identification of new anticonvulsant compounds from myxobacterial origin, using zebrafish larvae as the primary screening model. Methods: A library of 242 myxobacterial compounds from the Helmholtz Centre for Infection Research was screened for neuroactivity by the zebrafish photomotor response (PMR) assay. Next, neuroactive hits were screened for anticonvulsant activity by the zebrafish pentylenetetrazole (PTZ) seizure assay. Anticonvulsant activity was further investigated by local field potential (LFP) recordings of the zebrafish midbrain to evaluate the effect of a compound on PTZ-induced epileptiform discharges. Finally, anticonvulsant activity was investigated in the mouse timed i.v. PTZ assay to investigate activity in the mouse model. Results: 56 myxobacterial compounds were identified as neuroactive by the PMR assay. 24 selected neuroactive hits were screened for anticonvulsant activity by the zebrafish PTZ assay. 8 compounds were identified as anticonvulsant hits and confirmed for their activity. Among them, apicularen A significantly reduced PTZ-induced seizure behavior with high efficacy in a concentration-dependent manner and significantly reduced PTZ-induced epileptiform discharges. Moreover, apicularen A significantly increased the PTZ dose needed to trigger forelimb clonus in the mouse timed i.v. PTZ assay. Conclusions: Myxobacteria are increasingly recognized as producers of bioactive secondary metabolites and can be considered as a rich source for drug discovery. In this study, we identified for the first time anticonvulsant myxobacterial compounds using a zebrafish-based screening approach. The anticonvulsant activity of apicularen A was verified by LFP recordings of the zebrafish midbrain and confirmed in the mouse timed i.v. PTZ model. Our results not only support the potential of myxobacterial compounds, but expand their utility as an interesting source for anti-epileptic drug discovery.

Jaar van publicatie:2015