Andreev YA et al. (2018), Analgesic Activity of Acid-Sensing Ion Channel ...

XB-ART-55773

Mar Drugs 2018 Dec 12;1612:. doi: 10.3390/md16120500.

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Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds.

Andreev YA , Osmakov DI , Koshelev SG , Maleeva EE , Logashina YA , Palikov VA , Palikova YA , Dyachenko IA , Kozlov SA .

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Acid-sensing ion channel 3 (ASIC3) makes an important contribution to the development and maintenance of inflammatory and acid-induced pain. We compared different ASIC3 inhibitors (peptides from sea anemones (APETx2 and Ugr9-1) and nonpeptide molecules (sevanol and diclofenac)) in anti-inflammatory action and analgesic effects. All tested compounds had distinct effects on pH-induced ASIC3 current. APETx2 inhibited only transient current, whereas Ugr9-1 and sevanol decreased transient and sustained components of the current. The effect on mice was evaluated after administering an intramuscular injection in the acetic acid writhing pain model and the complete Freund's adjuvant-induced thermal hyperalgesia/inflammation test. The bell-shaped dependence of the analgesic effect was observed for APETx2 in the acetic acid-induced writhing test, as well as for sevanol and peptide Ugr9-1 in the thermal hyperalgesia test. This dependence could be evidence of the nonspecific action of compounds in high doses. Compounds reducing both components of ASIC3 current produced more significant pain relief than APETx2, which is an effective inhibitor of a transient current only. Therefore, the comparison of the efficacy of ASIC3 inhibitors revealed the importance of ASIC3-sustained currents' inhibition for promotion of acidosis-related pain relief.

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Species referenced: Xenopus laevis
Genes referenced: asic3

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	Figure 1. Comparison of ligands’ antagonistic effects on hASIC3 channels. Whole-cell currents were induced by pH drops and recorded at the holding potential −50 mV. (A) Effect of ligands on the transient component of current at conditioning pH 7.8. The control trace is shown first; (B) Effect of ligands on the sustained component at conditioning pH 7.3. The black line is the control trace, and the red line is the trace of activation in the presence of a ligand. Dose-response curves for transient (C) and sustained (D) currents’ inhibitions are shown. Data are shown as mean ± SEM (n = 4–6) and fitted with the logistic equation (solid lines).
	Figure 2. Open field experiments on mice. Administration of compounds at a 1 mg/kg dose intramuscularly was done 4 h before of the measurements. (A) Travelling distance and (B) locomotion activity presented as mean ± SEM for 5-min recording period (n = 6–7).
	Figure 3. Effects of ligands in an acetic acid-induced writhing test. Pretreatment of mice with APETx2, sevanol, and Ugr9-1 (2 h before testing) attenuated the response to the intraperitoneal administration of acetic acid. (A) Efficacy of ASIC3 antagonists at a dose of 1 mg/kg. (B–D) Dose-dependent chart of ligands’ effects: APETx2 (B), sevanol (C), and Ugr9-1 (D). Results are presented as mean ± SEM (n = 8). p < 0.01, * p < 0.001 versus saline group (ANOVA followed by a Tukey’s test).
	Figure 4. Effect of ligands on the CFA-induced thermal hyperalgesia test. Test was performed 2 h after intramuscular administration of ASIC3 antagonists. (A) Comparison between ligands at the dose of 1 mg/kg; (B–D) Dose-dependent chart of ligands’ effect. APETx2 (B), sevanol (C), and Ugr9-1 (D) reversed CFA-induced thermal hyperalgesia and prolonging withdrawal latency of the inflamed hind paw on a hot plate. Results are presented as mean ± SEM (n = 7–8). * p < 0.05, p < 0.01, * p < 0.001 versus saline group (ANOVA followed by a Tukey’s test).
	Figure 5. Anti-inflammatory effect of ligands. Paw oedema induced by CFA injection was estimated before the CFA and testing compounds administration and 2, 4, and 24 h after the intramuscular injection of diclofenac (A), APETx2 (B), sevanol (C), and Ugr9-1 (D). Results are presented as mean ± SEM (n = 7–8). * p < 0.05, p < 0.01, * p < 0.001 versus saline group (ANOVA followed by a Tukey’s test).

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	Figure 1. Comparison of ligands’ antagonistic effects on hASIC3 channels. Whole-cell currents were induced by pH drops and recorded at the holding potential −50 mV. (A) Effect of ligands on the transient component of current at conditioning pH 7.8. The control trace is shown first; (B) Effect of ligands on the sustained component at conditioning pH 7.3. The black line is the control trace, and the red line is the trace of activation in the presence of a ligand. Dose-response curves for transient (C) and sustained (D) currents’ inhibitions are shown. Data are shown as mean ± SEM (n = 4–6) and fitted with the logistic equation (solid lines).
	Figure 2. Open field experiments on mice. Administration of compounds at a 1 mg/kg dose intramuscularly was done 4 h before of the measurements. (A) Travelling distance and (B) locomotion activity presented as mean ± SEM for 5-min recording period (n = 6–7).
	Figure 3. Effects of ligands in an acetic acid-induced writhing test. Pretreatment of mice with APETx2, sevanol, and Ugr9-1 (2 h before testing) attenuated the response to the intraperitoneal administration of acetic acid. (A) Efficacy of ASIC3 antagonists at a dose of 1 mg/kg. (B–D) Dose-dependent chart of ligands’ effects: APETx2 (B), sevanol (C), and Ugr9-1 (D). Results are presented as mean ± SEM (n = 8). p < 0.01, * p < 0.001 versus saline group (ANOVA followed by a Tukey’s test).
	Figure 4. Effect of ligands on the CFA-induced thermal hyperalgesia test. Test was performed 2 h after intramuscular administration of ASIC3 antagonists. (A) Comparison between ligands at the dose of 1 mg/kg; (B–D) Dose-dependent chart of ligands’ effect. APETx2 (B), sevanol (C), and Ugr9-1 (D) reversed CFA-induced thermal hyperalgesia and prolonging withdrawal latency of the inflamed hind paw on a hot plate. Results are presented as mean ± SEM (n = 7–8). * p < 0.05, p < 0.01, * p < 0.001 versus saline group (ANOVA followed by a Tukey’s test).
	Figure 5. Anti-inflammatory effect of ligands. Paw oedema induced by CFA injection was estimated before the CFA and testing compounds administration and 2, 4, and 24 h after the intramuscular injection of diclofenac (A), APETx2 (B), sevanol (C), and Ugr9-1 (D). Results are presented as mean ± SEM (n = 7–8). * p < 0.05, p < 0.01, * p < 0.001 versus saline group (ANOVA followed by a Tukey’s test).