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Zebrafish-Based Screening of Antiseizure Plants Used in Traditional Chinese Medicine: Magnolia officinalis Extract and Its Constituents Magnolol and Honokiol Exhibit Potent Anticonvulsant Activity in a Therapy-Resistant Epilepsy Model
journal contribution
posted on 2020-02-20, 21:44 authored by Jing Li, Daniëlle Copmans, Michèle Partoens, Borbála Hunyadi, Walter Luyten, Peter de WitteWith the aim to discover
interesting lead compounds that could
be further developed into compounds active against pharmacoresistant
epilepsies, we first collected 14 medicinal plants used in traditional
Chinese medicine (TCM) against epilepsy. Of the six extracts that
tested positive in a pentylenetetrazole (PTZ) behavioral zebrafish
model, only the ethanol and acetone extracts from Magnolia
officinalis (M. officinalis) also showed
effective antiseizure activity in the ethylketopentenoate (EKP) zebrafish
model. The EKP model is regarded as an interesting discovery platform
to find mechanistically novel antiseizure drugs, as it responds poorly
to a large number of marketed anti-epileptics. We then demonstrated
that magnolol and honokiol, two major constituents of M. officinalis, displayed an effective behavioral and electrophysiological antiseizure
activity in both the PTZ and the EKP models. Out of six structural
analogues tested, only 4-O-methylhonokiol was active
and to a lesser extent tetrahydromagnolol, whereas the other analogues
(3,3′-dimethylbiphenyl, 2,2′-biphenol, 2-phenylphenol,
and 3,3′,5,5′-tetra-tert-butyl-[1,1′-biphenyl]-2,2′-diol)
were not consistently active in the aforementioned assays. Finally,
magnolol was also active in the 6 Hz psychomotor mouse model, an acute
therapy-resistant rodent model, thereby confirming the translation
of the findings from zebrafish larvae to mice in the field of epilepsy.
We also developed a fast and automated power spectral density (PSD)
analysis of local field potential (LFP) recordings. The PSD results
are in agreement with the visual analysis of LFP recordings using
Clampfit software and manually counting the epileptiform events. Taken
together, screening extracts of single plants employed in TCM, using
a combination of zebrafish- and mouse-based assays, allowed us to
identify allyl biphenol as a chemical scaffold for the future development
of compounds with potential activity against therapy-resistant epilepsies.