GABAA receptors as in vivo substrate for the anxiolytic action of valerenic acid, a major constituent of valerian root extracts

Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Neuropharmacology (Impact Factor: 5.11). 07/2008; 56(1):174-81. DOI: 10.1016/j.neuropharm.2008.06.013
Source: PubMed


Valerian extracts have been used for centuries to alleviate restlessness and anxiety albeit with unknown mechanism of action in vivo. We now describe a specific binding site on GABA(A) receptors with nM affinity for valerenic acid and valerenol, common constituents of valerian. Both agents enhanced the response to GABA at multiple types of recombinant GABA(A) receptors. A point mutation in the beta2 or beta3 subunit (N265M) of recombinant receptors strongly reduced the drug response. In vivo, valerenic acid and valerenol exerted anxiolytic activity with high potencies in the elevated plus maze and the light/dark choice test in wild type mice. In beta3 (N265M) point-mutated mice the anxiolytic activity of valerenic acid was absent. Thus, neurons expressing beta3 containing GABA(A) receptors are a major cellular substrate for the anxiolytic action of valerian extracts.

Download full-text


Available from: Andrea Barberis,
  • Source
    • "This good bioavailability is in line with the reported anxiolysis of VA after oral administration in mice (Benke et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Valerenic acid (VA) is a β2/3 subunit-specific modulator of γ-aminobutyric acid (GABA) type A (GABAA) receptors inducing anxiolysis. Here we analyze if VA-esters can serve as prodrugs and if different ester structures have different in vitro/in vivo effects. Modulation of GABAA receptors expressed in Xenopus oocytes was studied with 2- microelectrode-voltage-clamp. Anxiolytic effects of the VA- esters were studied on male C57BL/6N mice by means of the Elevated-Plus-Maze-test; anticonvulsant properties were deduced from changes in seizure threshold upon pentylenetetrazole-infusion. VA was detected in plasma confirming hydrolysis of the esters and release of VA in vivo. Esterification significantly reduced the positive allosteric modulation of GABAA (α1β3γ2S) receptors in vitro. In vivo, the studied VA-ester derivatives induced similar or even stronger anxiolytic and anticonvulsant action than VA. While methylation and propylation of VA resulted in faster onset of anxiolysis, the action of VA-ethylester was longer lasting, but occurred with a significant delay. The later finding is in line with the longer lasting anticonvulsant effects of this compound. The estimated VA plasma concentrations provided first insight into the release kinetics from different VA-esters. This might be an important step for its future clinical application as a potential non-sedative anxiolytic and anticonvulsant.
    European journal of pharmacology 03/2014; 735(100). DOI:10.1016/j.ejphar.2014.03.019 · 2.53 Impact Factor
  • Source
    • "Natural products from distinct structural classes including flavonoids [22] [23] [24] [25], terpenoids [26- 28], sesquiterpenes [29] [30] [31], diterpenes [32] , triterpene glycosides [33], polyacetylenes [34], (neo)lignans [28] [35], alkaloids [3] or (furano)coumarins [36] [37] have been shown to modulate GABA A receptors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The action of piperine (the pungent component of pepper) and its derivative SCT-66 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) on different gamma-aminobutyric acid (GABA) type A (GABAA) receptors, transient-receptor-potential-vanilloid-1 (TRPV1) receptors and behavioural effects were investigated. GABAA receptor subtypes and TRPV1 receptors were expressed in Xenopus laevis oocytes. Modulation of GABA-induced chloride currents (IGABA) by piperine and SCT-66 and activation of TRPV1 was studied using the two-microelectrode-voltage-clamp technique and fast perfusion. Their effects on explorative behaviour, thermoregulation and seizure threshold were analysed in mice. Piperine acted with similar potency on all GABAA receptor subtypes (EC50 range: 42.8 ± 7.6 μM (α2β2)–59.6 ± 12.3 μM (α3β2)). IGABA modulation by piperine did not require the presence of a γ2S-subunit, suggesting a binding site involving only α and β subunits. IGABA activation was slightly more efficacious on receptors formed from β2/3 subunits (maximal IGABA stimulation through α1β3 receptors: 332 ± 64% and α1β2: 271 ± 36% vs. α1β1: 171 ± 22%, p < 0.05) and α3-subunits (α3β2: 375 ± 51% vs. α5β2:136 ± 22%, p < 0.05). Replacing the piperidine ring by a N,N-diisobutyl residue (SCT-66) prevents interactions with TRPV1 and simultaneously increases the potency and efficiency of GABAA receptor modulation. SCT-66 displayed greater efficacy on GABAA receptors than piperine, with different subunit-dependence. Both compounds induced anxiolytic, anticonvulsant effects and reduced locomotor activity; however, SCT-66 induced stronger anxiolysis without decreasing body temperature and without the proconvulsive effects of TRPV1 activation and thus may serve as a scaffold for the development of novel GABAA receptor modulators.
    Biochemical pharmacology 04/2013; 85(12). DOI:10.1016/j.bcp.2013.04.017 · 5.01 Impact Factor
  • Source
    • " Valeriana officinalis L. Benke et al. (2009) have described GABA-A receptors containing the b3 subunit as the major target that mediates the anxiolytic action of valerenic acid and valerenol, common constituents of valerian root extracts. Moreover it was demonstrated that the b2 and the b3 (N265M) point mutations inhibited the GABA potentiating effect of valerenic acid on recombinant receptors strongly reducing the drug response. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epilepsy is a neurological disorder which has been recognized since antiquity. This paper evaluates the prophylactic and therapeutic remedies used by folk medicine to cure epilepsy in Italy. The data has been collected by reviewing written sources of physicians, ethnographers, folklorists between the late nineteenth and mid twentieth century. This approach lead to unearthing of 78 heterogeneous healing methods that have been divided into 16 (20%) magical, 20 (26%) religious and 42 (54%) natural remedies. The latter has been subdivided into 18 (43%) animal remedies, 17 (40%) plant remedies and 7 (17%) other remedies. Religious and magical remedies were used with the conviction that they would be able to provide recovery from epilepsy and to ward off evil spirits which had taken possession of the sick. Insterestingly, the herbal remedies highlighted 12 (70%) plants that play or might play an important role with respect to the mechanisms that generate the epileptic seizures. This leads us to reconsider the historical significance of folk medicine, too often it is underestimated owing to its use of ineffective remedies, born of incompetence and superstition.
    Journal of ethnopharmacology 12/2012; 145(2). DOI:10.1016/j.jep.2012.11.043 · 3.00 Impact Factor
Show more