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Analysis of ?-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives.

ABSTRACT: Valerenic acid (VA)-a ?2/3-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 ?-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 ?1?1?2S, ?1?2?2S, or ?1?3?2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. ?2/3-selective VA derivatives such as VA-amide (VA-A) modulating ?1?3?2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and ?1?2?2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (?1?3?2S: VA: Emax = 632 ± 88%, n = 9 versus ?1?2?2S: 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 ?3-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 (?1?3?2S: VA-TET: EC50 = 6.0 ± 1.0 ?M, 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 ?2/3-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.

SUBMITTER: Khom S

PROVIDER: S-EPMC4885513 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Analysis of β-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives.

Khom S S Hintersteiner J J Luger D D Haider M M Pototschnig G G Mihovilovic M D MD Schwarzer C C Hering S S

The Journal of pharmacology and experimental therapeutics 20160418 3

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, ...[more]

PMID: 27190170

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Analysis of ?-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives.

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Analysis of β-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives.

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