Analysis of beta-Subunit-dependent GABA(A) Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives

作者：Khom S^*; Hintersteiner J; Luger D; Haider M; Pototschnig G; Mihovilovic M D; Schwarzer C^*; Hering S

来源：Journal of Pharmacology and Experimental Therapeutics, 2016, 357(3): 580-590.

DOI：10.1124/jpet.116.232983

Valerenic acid (VA)-a beta 2/3-selective GABA type A (GABA(A)) receptor modulator-displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed beta-subunit-dependent enhancement of GABA-induced chloride currents (I-GABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)induced seizure threshold and locomotion. Compound-induced I-GABA enhancement was determined in oocytes expressing alpha 1 beta 1 gamma 2S, alpha 1 beta 2 gamma 2S, or alpha 1 beta 1 gamma 2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. beta 2/3-selective VA derivatives such as VA-amide (VA-A) modulating alpha 1 beta 1 gamma 2S (VA-A: E-max = 972 +/- 69%, n = 6, P<0.05) and alpha 1 beta 1 gamma 2S receptors (E-max = 1119 +/- 72%, n = 6, P<0.05) more efficaciously than VA (alpha 1 beta 1 gamma 2S: VA: E-max = 632 +/- 88%, n = 9 versus alpha 1 beta 1 gamma 2S: VA: E-max = 721 +/- 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 +/- 6 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 +/- 6 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 +/- 6 1.9 mg/kg PTZ, P<0.05). Similarly, VA's methylamide (VA-MA) enhancing I-GABA through beta 3-containing receptors more efficaciously than VA (E-max = 1043 +/- 57%, P<0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of I-GABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (alpha 1 beta 1 gamma 2S: VA-TET: EC50 = 6.0 +/- 6 1.0 mu 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 beta 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.

• 出版日期2016-6