GABAA Receptor Binding Assays of Standardized Leonurus cardiaca and Leonurus japonicus Extracts as Well as Their Isolated Constituents

Abstract

A main traditional use of European Leonurus cardiaca and East Asian Leonurus japonicus is in the treatment of neurological disorders such as anxiety, depression, nervousness, and as a sedative for insomnia. However, their mechanism of action is still under discussion. As anxiety and depressive disorders are increasingly being recognized as connected to dysfunctions of the gamma-aminobutyric acid system, the in vitro effects of standardized L. cardiaca and L japonicus extracts as well as five of their isolated constituents, namely, the labdane-type isoleosibirin, the novel iridoid 7R-chloro-6-desoxy-harpagide, the phenylethanoid lavandulifolioside, and the N-containing compounds stachydrine and leonurine, on this type of neuronal receptor were investigated for the first time. Extracts of L. cardiaca and L. japonicus, characterized by reversed-phase high-performance liquid chromatography determination, as well as their above named isolated, possible active constituents of different chemical nature were tested in several receptor binding assays at rat GABAA receptors using [(3)H]-SR95 531 and [(3)H]-Ro-15-1788 (flumazenil)/diazepam control. The L. cardiaca and L. japonicus extracts as well as leonurine inhibited the concentration-dependent binding of [(3)H]-SR95 531 to the gamma-aminobutyric acid site of the gamma-aminobutyric acid type A receptor with a high binding affinity: IC50s 21 µg/ml, 46 µg/ml, and 15 µg/ml, respectively. In contrast, binding to the benzodiazepine site of the rat gamma-aminobutyric acid type A receptor had a 15 to 30 times lower binding affinity than to the gamma-aminobutyric acid site. The presented experiments provide hints that the neurological mechanism of action of L. cardiaca and L. japonicus may essentially be based on their interaction to the gamma-aminobutyric acid site of the gamma-aminobutyric acid type A receptor, while the benzodiazepine site most probably does not contribute to this effect. In the case of L. japonicus, these effects can be at least partially explained by its leonurine constituent, whereas the active principle of L. cardiaca, which does not contain leonurine, is subject to further research as none of the other investigated individual constituents displayed significant activity in the applied test system.

“Wild cannabis”: A review of the traditional use and phytochemistry of Leonotis leonurus

“…However, there is some doubt as to the validity of this claim since no experimental evidence has ever been published indicating that leonurine has been found to occur in L. leonurus, although it has been documented in a related species, Leonurus japonicus (Hayashi, 1962;Kong et al, 1976;Luo, 1985;Chen and Kwan, 2001) Moreover, in addition to the lack of scientific evidence for the occurrence of leonurine in L. leonurus, there is also no evidence indicating that leonurine exhibits a psychotropic activity similar to that of Cannabis. In fact, the only neuronal activity of leonurine that has been experimentally verified is an effect on the GABA A receptor, similar to that found for Valerian , Rauwald et al 2015.…”

Reassessment of the polar fraction of Stachys alopecuros (L.) Benth. subsp. divulsa (Ten.) Grande (Lamiaceae) from the Monti Sibillini National Park and its potential pharmacologic uses.

“…The presence of 11 was noteworthy since it is not an ubiquitous compound, especially in the Stachys genus where it has been recognized only in a few species such as S. lavandulifolia [36], S. sieboldii [15], and S. tymphaea [8]. This compound resulted to be a constituent of other systematically related genera such as Leonurus [37,38], Lagochilus [39], and Sideritis [40]. …”

“…The presence of antioxidant components resulted to have a primary role in neuroprotection and PhGs are well-known antioxidants. Species belonging to Leonurus genus, all containing (11) together with iridoids, have been largely used in the traditional Mongolian medicine for the treatment of diabetes mellitus [38] and in the treatment of neurological disorders such as anxiety, depression, and nervousness [37]. …”

Leonurus cardiaca L., das Echte Herzgespann

“…In der traditionellen Veterinärmedizin in Endometriose postuliert [11]. Leonurin bindet auch an den GABA A -Rezeptor mit hoher Affinität [12] und könnte damit anxiolytische Effekte erklären helfen, die in älteren Studien berichtet wurden [8].…”