Methanolic leaf and root extracts of the Hawaiian kava (Piper methysticum Forst.) cultivars, Mahakea, Nene, Purple Moi and PNG, were tested on binding affinities to CNS receptors including GABAA (GABA and benzodiazepine binding site), dopamine D2, opioid (mu and delta), serotonin (5-HT6 and 5-HT7) and histamine (H1 and H2). HPLC analysis was carried out in order to determine the amount of the main kavalactones kavain, 7,8-dihydrokavain, methysticin, 7,8-dihydromethysticin, yangonin and 5,6-demethoxyyangonin. The most potent binding inhibition was observed for leaf extracts to GABAA receptors (GABA binding site) with IC50 values of approximately 3 micrograms/ml, whereas root extracts were less active with IC50 values ranging from 5 micrograms/ml (Nene) to 87 micrograms/ml (Mahakea). Since the leaf extracts generally contained lower amounts of the kavalactones than the root extracts, there might exist additional substances responsible for these activities. Leaf extracts also inhibited binding to dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors more potently than the corresponding root extracts with IC50 values ranging from 1 to 100 micrograms/ml vs. > or = 100 micrograms/l, respectively. Significant differences in the potential of binding inhibition were also observed between cultivars. Binding to serotonin (5-HT6 and 5-HT7) and benzodiazepine receptors was only weakly inhibited by both root and leaf extracts of all four cultivars. In conclusion, our investigation indicates that the GABAA, dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors might be involved in the pharmacological action of kava extracts. Since the cultivars contained similar amounts of kavalactones, while their pharmacological activities differed markedly, other constituents may play a role in the observed activities. Additionally, leaves generally exhibited more potent binding inhibition than roots, therefore leaf of P. methysticum might be an interesting subject for further pharmacological studies.

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Background: Plant extracts have been used in traditional medicine for the treatment of various maladies including neurological diseases. Several central nervous system receptors have been demonstrated to interact with plant extracts and components affecting the pharmacology and thereby potentially playing a role in human disease and treatment. For instance, extracts from Hypericum perforatum (St. John’s wort) targeted several CNS receptors. Similarly, extracts from Piper nigrum, Stephania cambodica, and Styphnolobium japonicum exerted inhibition of agonist-induced activity of the human neurokinin-1 receptor. Methods: Different methods have been established for receptor binding and functional assays based on radioactive and fluorescence-labeled ligands in cell lines and primary cell cultures. Behavioral studies of the effect of plant extracts have been conducted in rodents. Plant extracts have further been subjected to mood and cognition studies in humans. Results: Mechanisms of action at molecular and cellular levels have been elucidated for medicinal plants in support of standardization of herbal products and identification of active extract compounds. In several studies, plant extracts demonstrated affinity to a number of CNS receptors in parallel indicating the complexity of this interaction. In vivo studies showed modifications of CNS receptor affinity and behavioral responses in animal models after treatment with medicinal herbs. Certain plant extracts demonstrated neuroprotection and enhanced cognitive performance, respectively, when evaluated in humans. Noteworthy, the penetration of plant extracts and their protective effect on the blood-brain-barrier are discussed. Conclusion: The affinity of plant extracts and their isolated compounds for CNS receptors indicates an important role for medicinal plants in the treatment of neurological disorders. Moreover, studies in animal and human models have confirmed a scientific basis for the application of medicinal herbs. However, additional investigations related to plant extracts and their isolated compounds, as well as their application in animal models and the conducting of clinical trials, are required.

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!A primary functional receptor screening assay was performed to examine the effects of methanolic extracts from ten Vietnamese medicinal plants on the human neurokinin-1 receptor expressed from Semliki Forest virus vectors in Chinese hamster ovary cells. Extracts from Piper nigrum, Stephania cambodica and Styphnolobium japonicum were found to exert inhibition on agonist-induced human neurokinin-1 receptor activity. Secondary assays and high performance liquid chromatography of the lead compounds addressed a possible association between pharmacological responses and these chemical compounds. Strong inhibition of human neurokinin-1 receptor was observed for extracts revealing the highest inhibitory potency for rotundine (tetrahydropalmatine) in S. cambodica extracts with IC 50 of 0.88 µM, followed by piperine and capsaicin in P. nigrum extracts with IC 50 values of approximately 2 µM, whereas rutin in S. japonicum extracts failed to inhibit hNK1R up to 100 µM. [4]. Since the hNK1R is known to be present in both the CNS and a number of other tissues and has been the target for development of drugs for migraine, emesis, anti-inflammation and psychiatric disorders [5,6], the potential interaction between plant extracts and the hNK1R is of significant interest. In this study, we employed the SFV system for overexpression of the hNK1R in CHO cells to investigate the effects of plant extracts on agonist-induced receptor activity. The methanolic extracts of the ten Vietnamese medicinal plants were subjected to a preliminary screening for their effects on receptors in presence of the agonist Substance P (SP). Extracts from three species, namely P. nigrum, S. japonicum and S. cambodica, were further selected and examined for probable associations between different geographical locations (accessions) with biological activity. Moreover, lead compounds of plant extracts from these three species were analyzed by HPLC and examined in functional receptor assays to elucidate whether extracts derived from different locations exert different activities in relation to their concentrations of lead compounds. HPLC was applied to determine the amount of piperine and capsaicin in P. nigrum, rotundine in S. cambodica, and rutin in S. japonicum collected from five different geographical locations (l " Fig. 1 and Table 1). The fruit extracts from P. nigrum, capsaicin and piperine showed the most consistent amounts of analyzed compounds ranging between 0.14 ± 0.01 % and 0.24 ± 0.01 % and between 1.51 ± 0.11 % and 2.22 ± 0.08 %, respectively. For tuber and root extracts from S. cambodica, the range of rotundine was between 0.98 ± 0.18 % and 4.69 ± 0.15 %, and moderately variable. In flower bud extracts from S. japonicum, rutin ranged from 0.17 ± 0.01 % to 6.14 ± 0.18 % showing the largest variation among analyzed compounds. The degree of variability within each species appeared to be influenced by not only the genotype, but also the plant parts examined. In this context, extracts of fruits (P. nigrum) showed the least variation, tu...