Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties
Acid-sensing ion channels (ASICs), which are present in almost all types of neurons, play an important role in physiological and pathological processes. The ASIC1a subtype is the most sensitive channel to the medium’s acidification, and it plays an important role in the excitation of neuro...
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doaj-3f105622b2804cd6a61e8bc11553e8412020-11-24T20:53:57ZengMDPI AGToxins2072-66512019-09-0111954210.3390/toxins11090542toxins11090542Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory PropertiesDmitry I. Osmakov0Sergey G. Koshelev1Victor A. Palikov2Yulia A. Palikova3Elvira R. Shaykhutdinova4Igor A. Dyachenko5Yaroslav A. Andreev6Sergey A. Kozlov7Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaBranch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, 142290 Pushchino, RussiaBranch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, 142290 Pushchino, RussiaBranch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, 142290 Pushchino, RussiaBranch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, 142290 Pushchino, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaAcid-sensing ion channels (ASICs), which are present in almost all types of neurons, play an important role in physiological and pathological processes. The ASIC1a subtype is the most sensitive channel to the medium’s acidification, and it plays an important role in the excitation of neurons in the central nervous system. Ligands of the ASIC1a channel are of great interest, both fundamentally and pharmaceutically. Using a two-electrode voltage-clamp electrophysiological approach, we characterized lindoldhamine (a bisbenzylisoquinoline alkaloid extracted from the leaves of <i>Laurus nobilis</i> L.) as a novel inhibitor of the ASIC1a channel. Lindoldhamine significantly inhibited the ASIC1a channel’s response to physiologically-relevant stimuli of pH 6.5−6.85 with IC<sub>50</sub> range 150−9 μM, but produced only partial inhibition of that response to more acidic stimuli. In mice, the intravenous administration of lindoldhamine at a dose of 1 mg/kg significantly reversed complete Freund’s adjuvant-induced thermal hyperalgesia and inflammation; however, this administration did not affect the pain response to an intraperitoneal injection of acetic acid (which correlated well with the function of ASIC1a in the peripheral nervous system). Thus, we describe lindoldhamine as a novel antagonist of the ASIC1a channel that could provide new approaches to drug design and structural studies regarding the determinants of ASIC1a activation.https://www.mdpi.com/2072-6651/11/9/542acid-sensing ion channel subtype 1abisbenzylisoquinoline alkaloidlindoldhaminenociceptioninflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dmitry I. Osmakov Sergey G. Koshelev Victor A. Palikov Yulia A. Palikova Elvira R. Shaykhutdinova Igor A. Dyachenko Yaroslav A. Andreev Sergey A. Kozlov |
spellingShingle |
Dmitry I. Osmakov Sergey G. Koshelev Victor A. Palikov Yulia A. Palikova Elvira R. Shaykhutdinova Igor A. Dyachenko Yaroslav A. Andreev Sergey A. Kozlov Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties Toxins acid-sensing ion channel subtype 1a bisbenzylisoquinoline alkaloid lindoldhamine nociception inflammation |
author_facet |
Dmitry I. Osmakov Sergey G. Koshelev Victor A. Palikov Yulia A. Palikova Elvira R. Shaykhutdinova Igor A. Dyachenko Yaroslav A. Andreev Sergey A. Kozlov |
author_sort |
Dmitry I. Osmakov |
title |
Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties |
title_short |
Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties |
title_full |
Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties |
title_fullStr |
Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties |
title_full_unstemmed |
Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties |
title_sort |
alkaloid lindoldhamine inhibits acid-sensing ion channel 1a and reveals anti-inflammatory properties |
publisher |
MDPI AG |
series |
Toxins |
issn |
2072-6651 |
publishDate |
2019-09-01 |
description |
Acid-sensing ion channels (ASICs), which are present in almost all types of neurons, play an important role in physiological and pathological processes. The ASIC1a subtype is the most sensitive channel to the medium’s acidification, and it plays an important role in the excitation of neurons in the central nervous system. Ligands of the ASIC1a channel are of great interest, both fundamentally and pharmaceutically. Using a two-electrode voltage-clamp electrophysiological approach, we characterized lindoldhamine (a bisbenzylisoquinoline alkaloid extracted from the leaves of <i>Laurus nobilis</i> L.) as a novel inhibitor of the ASIC1a channel. Lindoldhamine significantly inhibited the ASIC1a channel’s response to physiologically-relevant stimuli of pH 6.5−6.85 with IC<sub>50</sub> range 150−9 μM, but produced only partial inhibition of that response to more acidic stimuli. In mice, the intravenous administration of lindoldhamine at a dose of 1 mg/kg significantly reversed complete Freund’s adjuvant-induced thermal hyperalgesia and inflammation; however, this administration did not affect the pain response to an intraperitoneal injection of acetic acid (which correlated well with the function of ASIC1a in the peripheral nervous system). Thus, we describe lindoldhamine as a novel antagonist of the ASIC1a channel that could provide new approaches to drug design and structural studies regarding the determinants of ASIC1a activation. |
topic |
acid-sensing ion channel subtype 1a bisbenzylisoquinoline alkaloid lindoldhamine nociception inflammation |
url |
https://www.mdpi.com/2072-6651/11/9/542 |
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