RT Journal Article
T1 Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A2 and Azaspirofuran A.
A1 Copmans, Daniëlle
A1 Rateb, Mostafa
A1 Tabudravu, Jioji N
A1 Pérez-Bonilla, Mercedes
A1 Dirkx, Nina
A1 Vallorani, Riccardo
A1 Diaz, Caridad
A1 Pérez Del Palacio, José
A1 Smith, Alan J
A1 Ebel, Rainer
A1 Reyes, Fernando
A1 Jaspars, Marcel
A1 de Witte, Peter A M
K1 Aspergillus fumigatus
K1 Epilepsy
K1 antiseizure drug discovery
K1 azaspirofuran A
K1 marine drug discovery
K1 pseurotin A2
AB In search for novel antiseizure drugs (ASDs), the European FP7-funded PharmaSea project used zebrafish embryos and larvae as a drug discovery platform to screen marine natural products to identify promising antiseizure hits in vivo for further development. Within the framework of this project, seven known heterospirocyclic γ-lactams, namely, pseurotin A, pseurotin A2, pseurotin F1, 11- O-methylpseurotin A, pseurotin D, azaspirofuran A, and azaspirofuran B, were isolated from the bioactive marine fungus Aspergillus fumigatus, and their antiseizure activity was evaluated in the larval zebrafish pentylenetetrazole (PTZ) seizure model. Pseurotin A2 and azaspirofuran A were identified as antiseizure hits, while their close chemical analogues were inactive. Besides, electrophysiological analysis from the zebrafish midbrain demonstrated that pseurotin A2 and azaspirofuran A also ameliorate PTZ-induced epileptiform discharges. Next, to determine whether these findings translate to mammalians, both compounds were analyzed in the mouse 6 Hz (44 mA) psychomotor seizure model. They lowered the seizure duration dose-dependently, thereby confirming their antiseizure properties and suggesting activity against drug-resistant seizures. Finally, in a thorough ADMET assessment, pseurotin A2 and azaspirofuran A were found to be drug-like. Based on the prominent antiseizure activity in both species and the drug-likeness, we propose pseurotin A2 and azaspirofuran A as lead compounds that are worth further investigation for the treatment of epileptic seizures. This study not only provides the first evidence of antiseizure activity of pseurotins and azaspirofurans, but also demonstrates the value of the zebrafish model in (marine) natural product drug discovery in general, and for ASD discovery in particular.
YR 2018
FD 2018-04-19
LK http://hdl.handle.net/10668/12371
UL http://hdl.handle.net/10668/12371
LA en
DS RISalud
RD Apr 19, 2025