title: Inhibitory effects of oenanthotoxin analogues on GABAergic currents in cultured rat hippocampal neurons depend on the polyacetylenes' polarity.
abstract: Oenanthotoxin (OETX) and dihydro-OETX are polyacetylenic diols occurring in Oenanthe crocata and are known to exert proconvulsant effects. We have recently demonstrated that these compounds downregulated GABAergic currents (Appendino et al., 2009) and that OETX induced open channel block and allosterically modulated GABA(A) receptors (Wyrembek et al., 2010). O. crocata also contains several minor OETX analogues and in the present study we tested whether their effect on GABA(A) receptors depends on the compounds' polarity. We investigated a series of five polyacetylenes characterized by a higher lipophylicity than OETX, (1-acetyl-2,3-dihydrooenanthotoxin - X1, 14-acetyloenanthotoxin-X2, 1-deoxyoenanthotoxin - X3, 14-deoxyoenanthotoxin - X4, 14-dehydro-1-deoxyOETX - X5, polarity sequence: X1>X2>X3>X4>X5). Their effects were tested first on miniature inhibitory postsynaptic currents (mIPSCs). All but X3, significantly decreased the mIPSC amplitudes while X1, X2, X4 decreased, and X3 and X5 increased the mIPSC frequency. The lack of a clear correlation between the compounds' polarity and their effect on mIPSCs might result from their presynaptic effects. We thus considered their impact on current responses to exogenous GABA applications. Amplitude reduction of current responses was most prominent for X1 and virtually absent for X5 indicating a dependence on the compound's polarity. Only X1 and X2 showed open channel block, while the kinetics of currents were affected only by X1 which further supports a dependence of the drug's effects on their polarity. In conclusion, GABA(A) receptors are inhibited and allosterically modulated by naturally occurring OETX analogues (except X5) and these effects are positively correlated with the compounds' polarity.
authors.affiliation: Laboratory of Neuroscience, Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 3, 50-358 Wrocław, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Wyrembek
authors.forename: Roberto
authors.initials: R
authors.lastname: Negri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Mozrzymas
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D002478:Cells, Cultured; D003292:Convulsants / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D055808:Drug Discovery; D053281:Enediynes / Q000737:chemistry* / Q000494:pharmacology; D005233:Fatty Alcohols / Q000737:chemistry* / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D031050:Oenanthe / Q000737:chemistry; D018517:Plant Roots / Q000737:chemistry; D053279:Polyynes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D053281:Enediynes; D005233:Fatty Alcohols; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D053279:Polyynes; C010719:enanthotoxin