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

• Published in: Toxins Vol. 11; no. 9; p. 542
• Main Authors: Osmakov, Dmitry I, Koshelev, Sergey G, Palikov, Victor A, Palikova, Yulia A, Shaykhutdinova, Elvira R, Dyachenko, Igor A, Andreev, Yaroslav A, Kozlov, Sergey A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.09.2019; MDPI
• Subjects: Acetic Acid; Acid Sensing Ion Channel Blockers - pharmacology; Acid Sensing Ion Channel Blockers - therapeutic use; Acid Sensing Ion Channels - physiology; acid-sensing ion channel subtype 1a; Acidification; Acidity; Acidosis; Acids; Alkaloids; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Benzene Derivatives - pharmacology; Benzene Derivatives - therapeutic use; Bisbenzylisoquinoline; bisbenzylisoquinoline alkaloid; Blood; Brain damage; Central nervous system; Drug development; Drug dosages; Female; Freund's Adjuvant; Hot Temperature - adverse effects; Hyperalgesia; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Intravenous administration; Ion channels; lindoldhamine; Male; Mice; Nervous system; Neurons; nociception; Oocytes - physiology; Pain; Pain - chemically induced; Pain - drug therapy; Pain perception; Peripheral nervous system; Physiology; Quinolines - pharmacology; Quinolines - therapeutic use; Sodium channels; Stimuli; Xenopus laevis; nociception; acid-sensing ion channel subtype 1a; bisbenzylisoquinoline alkaloid; lindoldhamine; inflammation
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins11090542

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 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 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.