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J Pharmacol Exp Ther
2016 Jun 01;3573:580-90. doi: 10.1124/jpet.116.232983.
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Analysis of β-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives.
Khom S
,
Hintersteiner J
,
Luger D
,
Haider M
,
Pototschnig G
,
Mihovilovic MD
,
Schwarzer C
,
Hering S
.
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Valerenic acid (VA)-a β2/3-selective GABA type A (GABAA) receptor modulator-displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed β-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1β1γ2S, α1β2γ2S, or α1β3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. β2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1β3γ2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and α1β2γ2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (α1β3γ2S: VA: Emax = 632 ± 88%, n = 9 versus α1β2γ2S: VA: Emax = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P < 0.05). Similarly, VA's methylamide (VA-MA) enhancing IGABA through β3-containing receptors more efficaciously than VA (Emax = 1043 ± 57%, P < 0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (α1β3γ2S: VA-TET: EC50 = 6.0 ± 1.0 μM, P < 0.05; VA-TET: 0.3 mg/kg: 47.3 ± 0.5 mg/kg PTZ versus VA: 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ, P < 0.05). At higher doses (≥10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. In contrast, unselective VA derivatives induced anticonvulsive effects only at high doses (30 mg/kg) or did not display any behavioral effects. Our data indicate that the β2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg/kg), whereas impairment of locomotion was observed at doses ≥10 mg/kg.
Fig. 1. VA and VA derivatives. Structural formulae of studied valerenic acid (VA) and VA derivatives are illustrated.
Fig. 2. β-Subunit-dependent IGABA enhancement by VA and VA derivatives. Concentration-dependent modulation of GABAA receptors composed of α1β3γ2S (dashed line), α1β2γ2S (▪), and α1β1γ2S (♦) subunits by (A) VA (data for enhancement of α1β3γ2S receptors taken from (Luger et al., 2015), (C) VA-A, (E) VA-MA, and (G) VA-TET. Data were fitted by nonlinear regression as described in Materials and Methods. Maximal potentiation of IGABA (Emax), EC50 values, Hill-coefficients (nH) and number of experiments for each compound on α1β1γ2S, α1β2γ2S and α1β3γ2S receptors are summarized in Table 1. Each data point represents a mean ± S.E.M from at least 3 different oocytes from 2 different frog batches. IGABA potentiation at 300 µM (α1β3γ2S receptors) for VA and VA-A, respectively, was excluded from the fit. Typical traces for the enhancement of GABA-induced chloride currents (IGABA, EC3-7, single bar) by 10 µM of (B) VA, (D) VA-A, (F) VA-MA, and (H) VA-TET (double bar; indicating coapplication of GABA and compound) at the indicated GABAA receptor subtype are illustrated.
Fig. 3. β-Subunit-dependent IGABA modulation by VA derivatives. Concentration-response curves for the IGABA enhancement through (●) α1β3γ2S, (▪) α1β2γ2S, and (♦) α1β1γ2S channels by VA derivatives (A) VA-CN, (C) VA-EA, (E) VA-DMA, and (G) VA-DEA. Data were fitted by nonlinear regression as described in Materials and Methods. Maximal potentiation of IGABA (Emax), EC50 values, Hill-coefficients (nH), and number of experiments for each compound on α1β1γ2S, α1β2γ2S, and α1β3γ2S receptors are summarized in Table 1. Each data point represents a mean ± S.E.M. from at least 3 different oocytes from 2 different frog batches. Typical current traces for the enhancement of GABA-induced chloride currents (IGABA, EC3-7, single bar) by 10 µM of (B) VA-CN, (D) VA-EA, (F) VA-DMA, and (H) VA-DEA (double bar; indicating coapplication of GABA and compound) at the indicated GABAA receptor subtype are illustrated.
Fig. 4. Anticonvulsive effects of VA and VA derivatives. Elevation of seizure threshold upon tail-vein infusion of PTZ 30 min after intraperitoneal application of (A) VA is illustrated. The dotted line represents the averaged seizure threshold of saline-treated control animals. Effect on PTZ-induced seizure threshold 30 min after intraperitoneal application by the VA derivatives (B) VA-A, (C) VA-TET, (D) VA-MA, (E) VA-DMA, (F) VA-EA, (G) VA-DEA, and (H) VA-CN is compared with VA (dashed line, ○) and control animals (dotted line). Each data point represents a mean ± S.E.M from at least 3 mice. Statistical significance (P values < 0.05 were accepted as significant; *P < 0.05, **P < 0.01, and ***P < 0.001) against VA was calculated by one-way ANOVA followed by a Bonferroni post hoc mean comparison.
Fig. 5. Effects on locomotion by VA and VA derivatives in the open-field test (OF) test. Black bars indicate the total distance covered in the OF test 30 minutes after intraperitoneal application of (A) VA, (B) VA-A, (C) VA-TET, (D) VA-MA, (E) VA-CN, (F) VA-DMA, (G) VA-EA, and (H) (VA-DEA) at the indicated doses compared with saline-treated control animals (white bars in all panels). Each bar represents a mean ± S.E.M. from at least 10 different mice. Statistical significance (P values < 0.05 were accepted as significant; *P < 0.05 and ***P < 0.001) against saline-treated control animals was calculated by one-way ANOVA followed by a Bonferroni post hoc mean comparison.
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