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Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties.
Osmakov DI
,
Koshelev SG
,
Palikov VA
,
Palikova YA
,
Shaykhutdinova ER
,
Dyachenko IA
,
Andreev YA
,
Kozlov SA
.
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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.
Figure 1. Lindoldhamine (LIN)’s effects on rat ASIC1a. (A) LIN’s chemical structure. (B) LIN’s predicted (cambered and flex) 3D structure (from PubChem; CID 10370752). Carbon atoms are in grey, hydrogen atoms in white, oxygen atoms\in red, and nitrogen atoms in blue. (С) The inhibitory effect that LIN (300 μM) had on the ASIC1a channel’s activation by fast external solution acidification from pH 7.4 to the corresponding pH stimulus. The black traces are the control current; the red traces are the current obtained after 15 s of LIN pre-application. All presented traces are for a single cell.
Figure 2. Dose-response curves for LIN’s inhibitory activity on ASIC1a currents. The colored curves denote the corresponding pH stimuli that activate the channel, relative to the conditioning pH of 7.4. Each point is the mean ± SEM of five measurements. The data were fitted using the F1 logistic equation (see the Materials and Methods Section for details).
Figure 3. The pH dependence of the ASIC1a activation by protons alone (black line) and with the co-application of protons and 0.3 mM of LIN (red line). The ASIC1a channel was held at pH 7.4 and then activated by various acidic stimuli. The relative current is the amplitude of the peak current that the acidic stimuli evoked, normalized to the maximum amplitude (which we calculated for each cell via individual fitting). The data are presented as the mean ± SEM (n = 5).
Figure 4. LIN activity in animal models. (A) LIN’s anti-inflammatory effect. We induced paw edema via complete Freund’s adjuvant (CFA) injection and estimated values before the administration of the CFA and the testing compound. LIN (1 mg/kg, i.v.) significantly reduced edema, even 24 h after injection. (B) LIN’s reversal of thermal hyperalgesia. LIN (1 mg/kg, i.v., 30 min before testing) significantly reversed CFA-induced thermal hyperalgesia and prolonged the withdrawal latency for an inflamed hind paw placed on a hot plate. (C) LIN’s effect on the writhing test. Pretreatment of mice with LIN (1 mg/kg, i.v., 30 min before testing) did not have any significant effect on the results of the writhing test, which involved the intraperitoneal administration of acetic acid. The results are presented as the mean ± SEM (n = 5–8); the p-values of the LIN group vs. the saline group are based on an analysis of variance and on Tukey’s test. * p < 0.05, ** p < 0.01.
Alijevic,
Subtype-specific modulation of acid-sensing ion channel (ASIC) function by 2-guanidine-4-methylquinazoline.
2012, Pubmed,
Xenbase
Alijevic,
Subtype-specific modulation of acid-sensing ion channel (ASIC) function by 2-guanidine-4-methylquinazoline.
2012,
Pubmed
,
Xenbase
Andreev,
Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds.
2018,
Pubmed
,
Xenbase
Atanasov,
Discovery and resupply of pharmacologically active plant-derived natural products: A review.
2015,
Pubmed
Baron,
Pharmacology of acid-sensing ion channels - Physiological and therapeutical perspectives.
2015,
Pubmed
Benson,
Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons.
2002,
Pubmed
Besson,
Pharmacological modulation of Acid-Sensing Ion Channels 1a and 3 by amiloride and 2-guanidine-4-methylquinazoline (GMQ).
2017,
Pubmed
,
Xenbase
Bhagya,
Tetrandrine--A molecule of wide bioactivity.
2016,
Pubmed
Bohlen,
A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain.
2011,
Pubmed
,
Xenbase
Chia,
Effect of isoquinoline alkaloids of different structural types on antiplatelet aggregation in vitro.
2006,
Pubmed
Coryell,
Restoring Acid-sensing ion channel-1a in the amygdala of knock-out mice rescues fear memory but not unconditioned fear responses.
2008,
Pubmed
Diochot,
Black mamba venom peptides target acid-sensing ion channels to abolish pain.
2012,
Pubmed
,
Xenbase
Duan,
Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis.
2011,
Pubmed
Duan,
Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity.
2007,
Pubmed
Fournet,
Trypanocidal bisbenzylisoquinoline alkaloids are inhibitors of trypanothione reductase.
1998,
Pubmed
Frias,
Capsaicin, Nociception and Pain.
2016,
Pubmed
Friese,
Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system.
2007,
Pubmed
Gründer,
Biophysical properties of acid-sensing ion channels (ASICs).
2015,
Pubmed
Ishikita,
Proton-binding sites of acid-sensing ion channel 1.
2011,
Pubmed
Karczewski,
Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2.
2010,
Pubmed
Khalifa,
The novel steroidal alkaloids dendrogenin A and B promote proliferation of adult neural stem cells.
2014,
Pubmed
Lardner,
The effects of extracellular pH on immune function.
2001,
Pubmed
Laurent,
Sites of Anesthetic Inhibitory Action on a Cationic Ligand-Gated Ion Channel.
2016,
Pubmed
Leng,
Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke?
2014,
Pubmed
Liu,
Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy.
2016,
Pubmed
Logashina,
Peptide from Sea Anemone Metridium senile Affects Transient Receptor Potential Ankyrin-repeat 1 (TRPA1) Function and Produces Analgesic Effect.
2017,
Pubmed
Logashina,
New Disulfide-Stabilized Fold Provides Sea Anemone Peptide to Exhibit Both Antimicrobial and TRPA1 Potentiating Properties.
2017,
Pubmed
Mamet,
Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels.
2002,
Pubmed
Materazzi,
Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel.
2013,
Pubmed
Mazzuca,
A tarantula peptide against pain via ASIC1a channels and opioid mechanisms.
2007,
Pubmed
Murebwayire,
Triclisia sacleuxii (Pierre) Diels (Menispermaceae), a potential source of acetylcholinesterase inhibitors.
2009,
Pubmed
NULL,
Removal of blood from laboratory mammals and birds. First report of the BVA/FRAME/RSPCA/UFAW Joint Working Group on Refinement.
1993,
Pubmed
Osmakov,
Acid-sensing ion channels and their modulators.
2014,
Pubmed
Osmakov,
Proton-independent activation of acid-sensing ion channel 3 by an alkaloid, lindoldhamine, from Laurus nobilis.
2018,
Pubmed
,
Xenbase
Osmakov,
Endogenous Isoquinoline Alkaloids Agonists of Acid-Sensing Ion Channel Type 3.
2017,
Pubmed
Osmakov,
Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline.
2019,
Pubmed
,
Xenbase
Osmakov,
Endogenous Neuropeptide Nocistatin Is a Direct Agonist of Acid-Sensing Ion Channels (ASIC1, ASIC2 and ASIC3).
2019,
Pubmed
Rash,
Acid-Sensing Ion Channel Pharmacology, Past, Present, and Future ….
2017,
Pubmed
Schuhmacher,
Expression of acid-sensing ion channels and selection of reference genes in mouse and naked mole rat.
2016,
Pubmed
Sherwood,
Endogenous arginine-phenylalanine-amide-related peptides alter steady-state desensitization of ASIC1a.
2008,
Pubmed
,
Xenbase
Sluka,
Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1.
2003,
Pubmed
Steen,
A dominant role of acid pH in inflammatory excitation and sensitization of nociceptors in rat skin, in vitro.
1995,
Pubmed
Stephan,
The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel.
2018,
Pubmed
,
Xenbase
Vick,
ASICs and neuropeptides.
2015,
Pubmed
Voilley,
Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors.
2001,
Pubmed
Vullo,
Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating.
2017,
Pubmed
Weber,
Bisbenzylisoquinoline Alkaloids.
2019,
Pubmed
Wemmie,
Acid-sensing ion channels in pain and disease.
2013,
Pubmed
Wu,
Sinomenine protects against ischaemic brain injury: involvement of co-inhibition of acid-sensing ion channel 1a and L-type calcium channels.
2011,
Pubmed