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Falcarindiol Allosterically Modulates GABAergic Currents in Cultured Rat Hippocampal Neurons

Falcarindiol Allosterically Modulates GABAergic Currents in Cultured Rat Hippocampal Neurons

Authors :
Wyrembek, Paulina
Negri, Roberto
Kaczor, Przemysław
Czyżewska, Marta
Appendino, Giovanni
Mozrzymas, Jerzy Wladyslaw
Source :
Journal of Natural Products; April 2012, Vol. 75 Issue: 4 p610-616, 7p
Publication Year :
2012

Abstract

Falcarindiol (1), a C-17 polyacetylenic diol, shows a pleiotropic profile of bioactivity, but the mechanism(s) underlying its actions are largely unknown. Large amounts of 1co-occur in water hemlock (Oenanthe crocata) along with the convulsant polyacetylenic toxin oenanthotoxin (2), a potent GABAAreceptor (GABAAR) inhibitor. Since these compounds are structurally and biogenetically related, it was considered of interest to evaluate whether 1could affect GABAergic activity, and for this purpose a model of hippocampal cultured neurons was used. Compound 1significantly increased the amplitude of miniature inhibitory postsynaptic currents, accelerated their onset, and prolonged the decay kinetics. This compound enhanced also the amplitude of currents elicited by 3 μM GABA and accelerated their fading, reducing, however, currents evoked by a saturating (10 mM) GABA concentration. Moreover, kinetic analysis of responses to 10 mM GABA revealed that 1upregulated the rate and extent of desensitization and slowed the current onset and deactivation. Taken together, these data show that 1exerts a potent modulatory action on GABAARs, possibly by modulating agonist binding and desensitization, overall potentially decreasing the toxicity of co-occurring GABA-inhibiting convulsant toxins.

Details

Language :
English
ISSN :
01633864 and 15206025
Volume :
75
Issue :
4
Database :
Supplemental Index
Journal :
Journal of Natural Products
Publication Type :
Periodical
Accession number :
ejs27052133
Full Text :
https://doi.org/10.1021/np2008522