Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism

Abstract

Extracts of the pepper plant kava (Piper methysticum) are effective in alleviating anxiety in clinical trials. Despite the long-standing therapeutic interest in kava, the molecular target(s) of the pharmacologically active constituents, kavalactones have not been established. γ-Aminobutyric acid type A receptors (GABAARs) are assumed to be the in vivo molecular target of kavalactones based on data from binding assays, but evidence in support of a direct interaction between kavalactones and GABAARs is scarce and equivocal. In this study, we characterised the functional properties of the major anxiolytic kavalactone, kavain at human recombinant α1β2, β2γ2L, αxβ2γ2L (x = 1, 2, 3 and 5), α1βxγ2L (x = 1, 2 and 3) and α4β2δ GABAARs expressed in Xenopus oocytes using the two-electrode voltage clamp technique. We found that kavain positively modulated all receptors regardless of the subunit composition, but the degree of enhancement was greater at α4β2δ than at α1β2γ2L GABAARs. The modulatory effect of kavain was unaffected by flumazenil, indicating that kavain did not enhance GABAARs via the classical benzodiazepine binding site. The β3N265M point mutation which has been previously shown to profoundly decrease anaesthetic sensitivity, also diminished kavain-mediated potentiation. To our knowledge, this study is the first report of the functional characteristics of a single kavalactone at distinct GABAAR subtypes, and presents the first experimental evidence in support of a direct interaction between a kavalactone and GABAARs.

GABA‐modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence

“…Through combining human evidence alongside preclinical (in vitro and in vivo) studies, reviews have also found strong indication that the anxiolytic effects of P. methysticum are due (at least in part) to the extract's multiple GABA‐ergic actions (Sarris et al, , ) Again, the conclusions drawn from these earlier reviews have been supported by recent studies, whereby GABA‐ergic mechanisms are investigated in more detail; in a recent tissue study, examining actions of a specific P. methysticum phytoconstituent “kavain” on expressed Xenopus oocytes (Chua et al, ) found that positive allosteric modulation occurred across all GABA‐A receptor subtypes examined (α1β2, β2γ2L, αxβ2γ2L ( x = 1,2,3, and 5), α1βxγ2L ( x = 1, 2, and 3), and α4β2δ), and where this action was not affected by administration of flumazenil, implicating sites other than BDZ receptors.…”

“…Baxter et al (); Boonen and Haberlein (); Chua et al (); Davies et al (); Gleitz et al (); He et al (); Jussofie et al (); Magura et al (); Martin et al (); Mathews et al ()…”

Kava drinking in traditional settings: Towards understanding effects on cognitive function

“…This complies with pharmacological guidelines (MediHerb, 1994), providing therapeutic value without causing cognitive impairment (Mills & Bone, 2005). Chua et al (2016) explain that kava contains a "group of structurally-related, lipophilic compounds known as kavalactones (or kavapyrones) … [which are] responsible for the clinical effects of kava" (p. 2). Those effects are reported to include antistress, anxiolytic, sedative, local anaesthetic, analgesic, anticonvulsant, and neuroprotective properties (Lim, 2016).…”

Kavalactones and Flavokavins Profiles Contribute to Quality Assessment of Kava (Piper methysticum G. Forst.), the Traditional Beverage of the Pacific

“…The occurrence of suspected hepatotoxicity in German acetonic extracts was most likely caused by non KLs compounds. KLs have been tested in different assays but were never found to be toxic [33,34]. FKB and FKA have been found to be potentially hepatotoxic for mice [35].…”