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HPLC-Based Activity Profiling for GABAA Receptor Modulators in Extracts: Validation of an Approach Utilizing a Larval Zebrafish Locomotor Assay

Moradi-Afrapoli, Fahimeh and Ebrahimi, Samad Nejad and Smiesko, Martin and Hamburger, Matthias. (2017) HPLC-Based Activity Profiling for GABAA Receptor Modulators in Extracts: Validation of an Approach Utilizing a Larval Zebrafish Locomotor Assay. Journal of Natural Products, 80 (5). pp. 1548-1557.

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Official URL: http://edoc.unibas.ch/56578/

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Abstract

Gamma-aminobutyric acid type A (GABAA) receptors are major inhibitory neurotransmitter receptors in the central nervous system and a target for numerous clinically important drugs used to treat anxiety, insomnia, and epilepsy. A series of allosteric GABAA receptor agonists was identified previously with the aid of HPLC-based activity profiling, whereby activity was tracked with an electrophysiological assay in Xenopus laevis oocytes. To accelerate the discovery process, an approach has been established for HPLC-based profiling using a larval zebrafish (Danio rerio) seizure model induced by pentylenetetrazol (PTZ), a pro-convulsant GABAA receptor antagonist. The assay was validated with the aid of representative GABAergic plant compounds and extracts. Various parameters that are relevant for the quality of results obtained, including PTZ concentration, the number of larvae, the incubation time, and the data analysis protocol, were optimized. The assay was then translated into an HPLC profiling protocol, and active compounds were tracked in extracts of Valeriana officinalis and Magnolia officinalis. For selected compounds the effects in the zebrafish larvae model were compared with data from in silico blood–brain barrier (BBB) permeability predictions, to validate the use for discovery of BBB-permeable natural products.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molecular Modeling (Vedani)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Pharmazeutische Biologie (Hamburger)
UniBasel Contributors:Hamburger, Matthias and Moradiafrapoli, Fahimeh and Smiesko, Martin
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
ISSN:0163-3864
e-ISSN:1520-6025
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:09 May 2018 06:33
Deposited On:09 May 2018 06:33

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