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Open AccessArticle

Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties

1
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
2
Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
3
Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, 142290 Pushchino, Russia
*
Author to whom correspondence should be addressed.
Toxins 2019, 11(9), 542; https://doi.org/10.3390/toxins11090542
Received: 29 July 2019 / Revised: 30 August 2019 / Accepted: 14 September 2019 / Published: 18 September 2019
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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 Laurus nobilis 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 IC50 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. View Full-Text
Keywords: acid-sensing ion channel subtype 1a; bisbenzylisoquinoline alkaloid; lindoldhamine; nociception; inflammation acid-sensing ion channel subtype 1a; bisbenzylisoquinoline alkaloid; lindoldhamine; nociception; inflammation
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Osmakov, D.I.; Koshelev, S.G.; Palikov, V.A.; Palikova, Y.A.; Shaykhutdinova, E.R.; Dyachenko, I.A.; Andreev, Y.A.; Kozlov, S.A. Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties. Toxins 2019, 11, 542.

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