Paulina Wyrembek†, Roberto Negri†‡, Przemysław Kaczor§, Marta Czyżewska†, Giovanni Appendino‡, and Jerzy Wladyslaw Mozrzymas*†§
† Laboratory of Neuroscience, Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 3, 50-358 Wrocław, Poland
‡ Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy
§ Department of Animal Molecular Physiology, Institute of Zoology, Wrocław University, Cybulskiego 30, 50-205 Wrocław, Poland
J. Nat. Prod., Article ASAP
DOI: 10.1021/np2008522
Publication Date (Web): March 20, 2012
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 1 co-occur in water hemlock (Oenanthe crocata) along with the convulsant polyacetylenic toxin oenanthotoxin (2), a potent GABAA receptor (GABAAR) inhibitor. Since these compounds are structurally and biogenetically related, it was considered of interest to evaluate whether 1 could affect GABAergic activity, and for this purpose a model of hippocampal cultured neurons was used. Compound 1 significantly 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 1 upregulated the rate and extent of desensitization and slowed the current onset and deactivation. Taken together, these data show that 1 exerts 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.
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