Toxicity of the synthetic polymeric 3-alkylpyridinium salt (APS3) is due to specific block of nicotinic acetylcholine receptors

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• 作者：Marjana Grandi?^a ; Romulo Ará ; oz^b ; Jordi Molgó ; ^b ; Tom Turk^c ; Kristina Sep?i?^c ; Evelyne Benoit^b ; Robert Frange?^a ; ^{robert.frangez@vf.uni-lj.si}
• 关键词：APS3 ; Motor endplate ; Nicotinic acetylcholine receptors ; Xenopus oocytes ; Mouse ; Rat
• 刊名：Toxicology
• 出版年：2013
• 出版时间：7 January, 2013
• 年：2013
• 卷：303
• 期：Complete
• 页码：25-33
• 全文大小：787 K

文摘

The in vivo and in vitro toxic effects of the synthetic polymeric 3-alkylpyridinium salt (APS3), from the Mediterranean marine sponge Reniera sarai, were evaluated on mammals, with emphasis to determine its mode of action. The median lethal doses of APS3 were 7.25 and higher that 20 mg/kg in mouse and rat, respectively. Intravenous administration of 7.25 and 20 mg/kg APS3 to rat caused a significant fall followed by an increase in mean arterial blood pressure accompanied by tachycardia. In addition, cumulative doses of APS3 (up to 60 mg/kg) inhibited rat nerve-evoked skeletal muscle contraction in vivo, with a median inhibitory dose (ID₅₀) of 37.25 mg/kg. When administrated locally by intramuscular injection to mouse, APS3 decreased the compound muscle action potential recorded in response to in vivo nerve stimulation, with an ID₅₀ of 0.5 mg/kg. In vitro experiments confirmed the inhibitory effect of APS3 on mouse hemidiaphragm nerve-evoked muscle contraction with a median inhibitory concentration (IC₅₀) of 20.3 ¦ÌM, without affecting directly elicited muscle contraction. The compound inhibited also miniature endplate potentials and nerve-evoked endplate potentials with an IC₅₀ of 7.28 ¦ÌM in mouse hemidiaphragm. Finally, APS3 efficiently blocked acetylcholine-activated membrane inward currents flowing through Torpedo nicotinic acetylcholine receptors (nAChRs) incorporated to Xenopus oocytes, with an IC₅₀ of 0.19 ¦ÌM. In conclusion, our results strongly suggest that APS3 blocks muscle-type nAChRs, and show for the first time that in vivo toxicity of APS3 is likely to occur through an antagonist action of the compound on these receptors.