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Valeriana officinalis L. (Valerianaceae) is one of the most reputed ancient medicinal plants used in modern phytotherapy and traditional medicine. Its root extract is one of the most effective herbal sedatives and tranquilizers, where the plant is also used for the treatment of gastrointestinal spasms. V. officinalis has complex phytochemistry consisting of the esterified iridoid derivatives known as valepotriates (e.g., valtrate, didrovaltrate, isovalerenic acid), sesquiterpenes (e.g., valerenic acid), flavonoids (e.g., linarin, apigenin), lignans (e.g., pinoresinol, hydroxypinoresinol), alkaloids (e.g., actinidine, valerine), triterpenes (e.g., ursolic acid), monoterpenes (e.g., borneol, bornyl acetate). Among them, valerenic acid is a marker compound for standardization of the root extracts of the plant and has been reported in many in vitro/in vivo studies to be responsible for anxiolytic action of the plant. Although modulation of gamma-aminobutyric acid (GABA) receptors has been revealed to be the leading mechanism of the plant-based on the existence of valerenic acid, several studies described the interaction of valerenic acid with glutamergic receptors. In addition to valerenic acid, isovaleric acid, didrovaltrate, borneol, and some lignans have also been proposed to contribute to the anxiolytic effect of the plant. In the current review, the data selectively scrutinized from the in vitro/in vivo studies about identifying anxiolytic molecular mechanisms of V. officinalis is focused.

Valeriana jatamansi Jones, an important medicinal herb of the Himalayan region, is an essential source of many therapeutic compounds and is traded/consumed in very high volume. The hypothesis of this study was that different seasons and light conditions may affect the content of medicinally valuable components with changes in the morpho-physiological attributes of the plant. Growing plants under suitable light conditions and harvesting of appropriate plant parts in optimum season is crucial for harnessing the full potential of the crop. Thus, the study was carried out to determine the seasonal response of V. jatamansi plants (genetically identical plants of same age) in terms of growth and phytochemical content under two different light conditions (full sunlight and 50% shade). During all seasons, growth parameters (plant height, leaf number, leaf area, relative water content, plant biomass) and the principle bioactive compounds (valerenic acid) were higher under shade conditions, while total flavonoids, tannins, phenolic compounds and antioxidant activities were higher under full sunlight conditions. HPLC analysis revealed that valerenic acid and most of the phenolic content were higher during summer season, especially in leaf part of the plant. The study suggested harvesting of V. jatamansi plants (especially leaf), during summer season to harness high quality raw material and to prevent loss of belowground parts. This strategy can be adopted by farmers for large scale cultivation of species.

Herbal medication used in the treatment of sleep disorders and anxiety often contain extracts of Valeriana officinalis or Passiflora incarnata. Valerenic acid in V. officinalis and apigenin, orientin, and vitexin in P. incarnata are thought to contribute to their therapeutic effect. It was the aim of this study to test whether these constituents of herbal extracts are interacting with the uptake of estrone 3-sulfate, pregnenolone sulfate, and dehydroepiandrosterone sulfate mediated by the uptake transporters organic anion transporting polypeptide 2B1 (OATP2B1) or organic anion transporting polypeptide 1A2 (OATP1A2). Madin-Darby canine kidney cells overexpressing OATP2B1 or OATP1A2 were used to determine the influence of the constituents on the cellular accumulation of the sulfated steroids. Subsequently, competitive counterflow experiments were applied to test whether identified inhibitors are also substrates of the transporters. Valerenic acid only interacted with OATP2B1, whereas apigenin, orientin, and vitexin interacted with OATP2B1 and OATP1A2. Competitive counterflow revealed that orientin is a substrate of both transporters, while apigenin was transported by OATP1A2 and vitexin by OATP2B1. In a next step, commercially available P. incarnata preparations were assessed for their influence on the transporters, revealing inhibition of transporter-mediated estrone 3-sulfate uptake. HPLC-UV-MS analysis confirmed the presence of orientin and vitexin in these preparations, thereby suggesting that these constituents are involved in the interaction. Our data indicate that constituents of P. incarnata may alter the function of OATP2B1 and OATP1A2, which could affect the uptake of other compounds relying on uptake mediated by the transporters.

Highlights • Valerenic acid modulates the neuropathological markers of Parkinson´s disease. • Valerenic acid attenuates neuroinflammation in a Parkinson´s disease model. • Astrocytes and cytokines are targets in the anti-inflammatory effect of valerenic acid. • The molecular docking confirms the interaction of valerenic acid with 5-HT5A receptors., Parkinson´s disease is the most important neuromotor pathology due to the prominent loss of dopaminergic neurons in the substantia nigra pars compacta. There is an inherent deficiency of dopamine in Parkinson´s disease, which is aggravated when neuroinflammatory processes are present. Several biomolecules are interesting candidates for the regulation of inflammation and possible neuroprotection, such as valerenic acid, one of the main components of Valeriana officinalis. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced mouse model of Parkinson's disease was developed to evaluate the motor effects of valerenic acid. The evaluation was carried out with four tests (an invert screen test for muscle strength, cross beam test, open field mobility test and lifting on hind legs test). Subsequently, the neuroinflammatory process was evaluated through ELISA of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and IFN-γ). The decreases in the inflammatory and neurodegenerative processes were evaluated by Western blot and immunohistochemistry analyses of the tissues, which included an evaluation of the tyrosine hydroxylase and GFAP proteins. Finally, the predicted mechanism of action of valerenic acid was supported by molecular docking calculations with the 5-HT5A receptor. The results indicate that the use of valerenic acid as a co-treatment decreases the neuroinflammation in Parkinson's disease induced by MPTP and provides evidence of a decrease in the evaluated pro-inflammatory cytokines and in the amount of GFAP in the mesencephalic area. Valerenic acid prevents neuroinflammation in a Parkinson's disease mouse model, which might reflect the neuroprotection of dopaminergic neurons with the recovery of motor ability.

Valerianа officinalis rhizomes whis roots, monocomponent and complex herbal drugs based on Valerianа officinalis, and the drug Corvalol containing chemically synthesized α-bromizovalerianic acid ethyl ester (ethyl bromovalerianate) are OTC drugs and are widely used. At the same time, in the database of drug adverse effects «Pharmacovigilance» AIS Roszdravnadzor from 2009 to 2018, 147 spontaneous reports of adverse reactions were registered when taking Valeriana rhizomes whis roots and Corvalol. The aim of the study was the analisis of spontaneous reporting about adverse reactions when taking Valeriana rhizomes and roots and the multi-component drug Corvalol in the database «Pharmacovigilance» AIS Roszdravnadzor and assessment of their compliance with the information in the instructions for medical use. It was reactions from the nervous system (lethargy, drowsiness, weakness, apathy, headache, dizziness, depression of consciousness, stupor, neurotoxicity, toxic encephalopathy), from the gastrointestinal tract (nausea, bitterness in the mouth, burning of the mucous membrane, belching, heartburn, appetite disorders), cardiovascular system (tachycardia) and allergic reactions (skin itching, skin flushing, rash, maculo-papular rash, urticaria, dermatitis, cheilitis, aphthous stomatitis, angioedema) in the reports. The sedative and anxiolytic effects of the leading biologically active component of rhizomes with valerian roots, valerenic acid, are mediated through modulation of the function of type-γ-aminobutyric acid receptors A. Experimentally confirmed that the mechanism of action of valerenic acid is similar to benzodiazepine drugs, which cause of a number of reported adverse neurological reactions. However, the range of complaints from patients cited in the reports is significantly wider than in the instructions for the medical use of these drugs. There is a need for further monitoring of reports and analysis of already received data and the addition of prescribing information of Valeriana rhizomes whis roots and Corvalol for ensuring safety requirements.

Background: Phytochemicals are group of compounds derived from plant resource and shown to have many pharmacological activities. Identification and quantification of chemical constituents in complex matrix of plant is a challenging task. LC-MS is the most prominent analytical technique for this purpose. Purpose: The aim of the present study is identification and quantification of bioactive compounds from Valeriana jatamansi using LC-MS and their in-vitro anti-proliferative screening. Materials and Methods: HPLC-ESI-QTOF-MS/MS separation for qualitative analysis was performed with the aid of an Agilent Poroshell 120 ECC18 column (2.7 μm, 50 mm × 4.6 mm). For quantitative analysis UPLC-ESI-QqQLIT−MS/MS separation was achieved on ACQUITY UPLC BEH™ C18 column (1.7 μm, 50 mm × 2.1 mm). The eluents were water with 0.1% formic acid (A) and acetonitrile (B). The anti-proliferative activity of samples of V. jatamansi on exponentially growing breast cancer cells was determined by the sulphorhodamine B (SRB) assay. Results: An efficient and sensitive LC-MS method was developed for metabolite profiling of five samples of V. jatamansi which resulted in the identification of forty-seven compounds by HPLC-ESI-QTOF-MS/MS. Nine bioactive compounds were quantified for the first time in leaves and roots of V. jatamansi using UPLC-ESI-QqQLIT−MS/MS. Quantitation method was also validated according to ICH guidelines. The correlation coefficient values (r2> 0.9873), LODs and LOQs for each analyte were < 15.7 and 47.6 ng/mL. The intra and inter-day precision variations (RSD) are

Valeriana jatamansi Jones and Hedychium spicatum Ham-ex-Smith are important medicinal herbs of the Himalayan region, which are highly demanded by pharmaceutical industries. Climatic variability especially increasing temperature and water deficit affects the growth and productivity of these species. In addition, increased temperature and water deficit may trigger the biosynthesis of medicinally important bioactive metabolites, which influence the quality of raw plant material and finished products. Therefore, V. jatamansi and H. spicatum plants were undertaken and subjected to different levels of drought (no irrigation), heat (35 °C), and combined stresses for investigating their physiological and metabolic responses. Both the treatments (individually and in combination) reduced relative water content, photosynthesis, carboxylation efficiency, chlorophyll content, while increased intracellular CO(2), malondialdehyde and H(2)O(2) content in both the species. Transpiration and stomatal conductance increased under heat and reduced under drought stress as compared to control. Water use efficiency was found to be increased under drought, while reduced under heat stress. Protein, proline, carotenoid content and antioxidant enzymes activities (superoxide dismutase, peroxidise, catalase) initially increased and thereafter decreased during late stages of stress. Exposure of plants to combined stress was more detrimental than individual stress. In V. jatamansi, exposure to drought stress significantly (p

Valerenic acid (VA) is a sesquiterpenoid and a phytoconstituent of the plant valerian used for sleeping disorders and anxiety. The frequency of using herbal components as therapeutic nutritional agents has increased lately. Their ability to improve redox homeostasis makes them a valuable approach against harmful xenobiotics. The purpose of this study was to evaluate the putative beneficial role of VA against the redox-perturbating role of the fungicide benomyl in HepG2 human liver cells in terms of oxidative stress in the cellular environment and in endoplasmic reticulum (ER). Benomyl increased cell total oxidant status and reactive oxygen species production and decreased total antioxidant status. The expression of genes coding for antioxidant molecules, namely, heme oxygenase-1, alpha glutathione s-transferase, NF-ĸB, and liver fatty acid binding protein, were decreased due to benomyl. VA ameliorated these effects. Benomyl also increased ER-stress-related molecules such as endoplasmic reticulum to nucleus signaling 1 protein, glucose-regulated protein 78, and caspase-12 levels, and VA acted also as a preventive agent. These results indicate that VA exerts ameliorative effects after benomyl-induced oxidative stress. VA, a widely used nutritional supplement, is a compound with potent antioxidant properties, which are valuable for the protection of cells against xenobiotic-induced oxidative damage.

Valeriana officinalis L. (Caprifoliaceae) has been traditionally used to treat mild nervous tension and sleep problems. The basis of these activities are mainly attributed to valerenic acid through the modulation of the GABA receptor. Moreover, V. officinalis is claimed to have other biological activities such as cardiovascular benefits, anticancer, antimicrobial and spasmolytic. The current review aims to update the biological and pharmacological studies (in vitro, in vivo and clinical trials) of V. officinalis and its major secondary metabolites in order to guide future research. Databases PubMed, Science Direct and Scopus were used for literature search including original papers written in English and published between 2014 and 2020. There have been identified 33 articles which met inclusion criteria. Most of these works were performed with V. officinalis extracts and only a few papers (in vitro and in vivo studies) evaluated the activity of isolated compounds (valerenic acid and volvalerenal acid K). In vitro studies focused on studying antioxidant and neuroprotective activity. In vivo studies and clinical trials mainly investigated activities on the nervous system (anticonvulsant activity, antidepressant, cognitive problems, anxiety and sleep disorders). Just few studies were focused on other different activities, highlight effects on symptoms of premenstrual and postmenopausal syndromes. Valeriana officinalis continues to be one of the medicinal plants most used by today's society for its therapeutic properties and whose biological and pharmacological activities continue to arouse great scientific interest as evidenced in recent publications. This review shows scientific evidence on traditional uses of V. officinalis on nervous system.

Valerenic acid and acetoxyvalerenic acid, a monocarboxylic acid, are bicyclic sesquiterpenoid phytochemicals present in various plant species of Valeriana. These phytoconstituents have been found to produce various pharmacological activities including sedative, antidepressant, neurotoxic, sedative, anxiolytic, with roles in brain-derived neurotrophic factor (BDNF) and gastrointestinal (GIT) motility, etc. Valerenic acid could also affect the condition of Alzheimer’s disease, as assumed through an increase in BDNF expression.

The use of new agricultural technologies such as soilless and aeroponic cultivation systems is a valuable approach to medicinal plant production. The present study investigated the prospects of enhancing yield and secondary metabolite production in Valeriana jatamansi under aeroponic cultivation using elicitors, such as yeast extract and methyl jasmonate. Plants were evaluated by measuring growth parameters, photosynthetic rate, and secondary metabolites contents (on dry weight basis). Maximum plant height (36.83 cm), leaf number (17.67), rootlet number (37.33), and rootlet length (6.90 cm) were observed at 0.5 mg/L yeast extract treatment; whereas treatment levels of 1.5 mg/L yeast, extract and 150 µM methyl jasmonate resulted in maximum leaf length (6.95 cm) and leaf width (5.43 cm), respectively. Maximum photosynthetic rate (5.4053 µmol m-2s-1) and stomatal conductance (0.0656 mmol m-2s-1) were recorded at treatment levels of 0.5 mg/L and 1.5 mg/L yeast extract respectively, whereas at 150 µM methyl jasmonate treatment, transpiration rate was 0.9046 mmol m-2s-1. In aeroponic cultivation, the maximum content of valerenic acid and hydroxy valerenic acid was detected in leaf (2.47 and 8.37 mg/g) and root (1.78 and 7.89 mg/g) at treatment levels of 100 µM and 150 µM methyl jasmonate, respectively. Acetoxy valerenic acid was highest in leaf (1.02 mg/g) at 1.5 mg/L yeast extract, and in the root (2.38 mg/g) at 150 µM methyl jasmonate. Gas chromatography-mass spectrometry analysis, identified twenty-eight volatile compounds in roots, of which three isovaleric acid (6.72-50.81%), patchouli alcohol (13.48-25.31%) and baldrinal (0.74-25.26%) were the major constituents. The results revealed that, besides roots, leaves could also be utilized as a prominent alternative source for targeted secondary metabolites. In conclusion, aeroponic cultivation offers year-round quality biomass production and ease to access subsequent roots harvest in V. jatamansi, to meet the demand of the pharmaceutical industries.

Glioblastoma multiform (GBM) continues to threaten people's lives due to the limited therapeutic strategies. As a new drug, Valerenic Acid suppresses the progression of GBM, however, the mechanism is largely unknown. Here, we found that Valerenic Acid can inhibit cell proliferation, migration and invasion of GBM cells by increasing innate immune signals such as enhancing ROS levels and activating the AMPK pathway. Inhibition of ROS by N-acetylcysteine (NAC) or attenuation of AMPK by Compound C could block Valerenic Acid-induced cell death. Additionally, the xenograft mouse model also confirmed that Valerenic Acid had anti-tumor effect. Together, our results provide compelling rational to develop Valerenic Acid as an anti-tumor agent against GBM patients.

Adipose tissue is an endocrine organ and its endocrine function is closely associated with type 2 diabetes mellitus. Valeriana officinalis (Valerian) exerts some physiological effects; however, its influence on adipocytes remains unclear. We investigated the effect of methanolic Valerian root extract (Vale) on 3T3-L1 adipocytes. Vale (1, 10, and 100 μg/mL) dose-dependently promoted adipocyte differentiation with increasing lipid accumulation. In addition, Vale significantly increased the mRNA levels in genes associated with adipocyte differentiation, including peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α , and adipocyte protein 2, in dose-dependent manner. Vale also significantly enhanced mRNA and protein levels in adiponectin. A PPARγ antagonist assay and a PPARγ binding assay revealed that Vale-induced increased adipocyte differentiation and adiponectin production were partly associated with direct binding to PPARγ. Valerenic acid, a characteristic component in Valerian, also demonstrated the ability to induce adipocyte differentiation and adiponectin secretion, suggesting that it is one of the functional components in Vale.

In addition to absorbing water and nutrients, the medicinal plant roots are sometimes responsible for the secondary metabolite production and/or accumulation. Root extension is, therefore, economically important in these plants. Here we used a hydroponic system to investigate the effects of exogenous methionine (Met) and phosphate (PO4) concentration on the biomass production and quality of valerian (Valeriana officinalis L.) root. The plants were grown in a cocopeat-perlite mixture and irrigated with nutrient solutions differed mainly in phosphate concentration (900, 1200, and 1500 μM) for four months. The valerian plants were exposed five times to 400 μM methionine either as foliar or root applications. Elevated phosphate concentration had a negative impact on yield and quality of valerian root, showing a 32 % reduction in root dry weight at 1500 compared with 900 μM phosphate. The maximum accumulation of essential oil (29 μL plant−1) and valerenic acid (11 mg plant−1) were also recorded at the lowest phosphate concentration (900 μM) coincided with the highest Zn absorption by the plants. Irrespective of the phosphate concentration, using Met, particularly in root application improved the measured plant traits. Met supplementation at the lowest phosphate concentration caused a 1.3-fold and 1.6-fold increase in the yield of the essential oil and valerenic acid, respectively. Overall, these findings indicate that an exogenous supply of Met at a relatively low phosphate concentration can considerably increase the yield and quality of valerian roots under hydroponic conditions.

Objetivo: Analisar o potencial ansiolítico do Ácido Valerênico mediante o acoplamento molecular in silico em receptores do tipo GABAA. Metodologia: Realizou-se um estudo do tipo quantitativo descritivo, com caráter experimental. A fim de se confirmar a validade da metodologia durante o acoplamento molecular, realizou-se um redocking utilizando a molécula de Diazepam nativa cristalografada com o receptor GABAA. As interações já apresentadas pelo Diazepam com o receptor, foram utilizadas para fins comparativos com as interações do Ácido Valerênico. As estruturas dos compostos foram obtidas por meio da plataforma PubChem. Para a representação tridimensional das estruturas foi utilizado o programa ChimeraX. Para a realização de todo o procedimento de docking foram utilizados os programas Biovia Discovery Studio, Avogadro, AutoDock Tools e AutoDock Vina. Resultados: Constatou-se que dentre todos os valores de afinidade demonstrados, levando-se em conta sua eletronegatividade, o Ácido Valerênico foi quem apresentou menor gasto energético. Nota-se também que o composto em questão viola apenas o parâmetro do LogP, o que o configura como um bom candidato a possível novo fármaco. Conclusão: Através do estudo in silico, foi possível a análise do potencial ansiolítico do Ácido Valerênico. Por meio da utilização do Diazepam e suas interações com o receptor GABAA como parâmetro, foi possível identificar que o Ácido Valerênico apresenta interações com gasto energético mínimo, e consequentemente valores aceitáveis de afinidade.

Ethnopharmacological relevance Valeriana fauriei root (VF) is a crude drug registered in the Japanese Pharmacopeia 17th Edition and a known substitute for V. officinalis (VO). Although VO has been pharmacologically evaluated for its sedative effects and mechanism of action, data regarding VF remain scarce. Aim of the study We compared the binding affinity of VF and VO extracts, as well as examined the active ingredients in the VF extract, on flunitrazepam sites of γ-aminobutyric acid receptor type A (GABAA receptor). Furthermore, we confirmed whether these active ingredients were distributed in the brain of mice orally administered the VF extract. Materials and methods We prepared the assay system to evaluate the binding activity of flunitrazepam sites of GABAA receptor using a 96-well plate and assessed the activities of VF and VO extracts. We then analyzed their constituents using HPLC with principal component analysis (PCA) and evaluated active ingredients correlated with their activities. The distribution of active ingredients in the plasma and brain of mice orally administered the VF extract prepared with different emulsifiers were analyzed by LC-MS/MS. Results The ethanol extract of VF exhibited significantly higher activity on flunitrazepam sites of GABAA receptor than VO. For the VF extract, kessyl glycol diacetate (KGD) was markedly associated with the binding activities; however, active ingredients included KGD, kessyl glycol 8-acetate (KG8), α-kessyl acetate (α-KA), and coniferyl isovalerate (CI). For VO, valerenic acid and five other compounds were associated with the binding affinity on flunitrazepam sites of GABAA receptor. On emulsifying the VF extract with a fat-soluble glycerin fatty acid ester, the plasma and brain distributions of KGD tended to be higher, those of KG8 were significantly more than 10-times higher, and those of α-KA was lower than those of the VF extract emulsified with water-soluble gum arabic, after oral administration in mice. Conclusions Based on the binding activity on flunitrazepam sites of GABAA receptor and brain distribution, KGD, KG8, and α-KA can be considered active ingredients of VF. The addition of a fat-soluble emulsifier promoted the absorption of KGD, the main active ingredient, and KGD was metabolized to KG8 in the body. The present results suggest a possible mechanism underlying the sedative effect for VF, and these three compounds can be used as marker compounds to evaluate the quality of VF products.

(Acetoxy-)valerenic acid and total essential oil content are important quality attributes of pharmacy grade valerian root (Valerianae radix). Traditional analysis of these quantities is time-consuming and necessitates (harmful) solvents. Here we investigated an application of attenuated total reflection Fourier transform infrared spectroscopy for extractionless analysis of these quality attributes on a representative sample comprising 260 wild-crafted individuals covering the Central European taxonomic diversity of the Valeriana officinalis L. s. l. species aggregate with its three major ploidy cytotypes (i.e., di-, tetra- and octoploid). Calibration models were built by orthogonal partial least squares regression for quantitative analysis of (acetoxy-)valerenic acid and total essential oil content. For the latter, we propose a simplistic protocol involving apolar extraction followed by gas chromatography as a reference method for multivariate calibration in order to handle the analysis of samples taken from individual plants. We found good predictive ability of chemometric models for quantification of valerenic acid, acetoxyvalerenic acid, total sesquiterpenoid acid, and essential oil content with a root mean squared error of cross-validation of 0.064, 0.043, and 0.09 and root mean squared error of prediction of 0.066, 0.057, and 0.09 (% content), respectively. Orthogonal partial least squares discriminant analysis revealed good discriminability between the most productive phenotype (i.e., the octoploid cytotype) in terms of sesquiterpenoid acids, and the less productive ones (i.e., di- and tetraploid). All in all, our results demonstrate the application of attenuated total reflection Fourier transform infrared spectroscopy for rapid, extractionless estimation of the most important quality attributes of valerian root and minimally invasive identification of the most productive phenotype in terms of sesquiterpenoid acids.

The plant natural product, valerenic acid (1) was chosen as a desirable scaffold for the generation of a novel screening library due to its drug-like physicochemical parameters (such as LogP, hydrogen bond donor/acceptor counts, and molecular weight). An 11-membered amide library (2-12) was subsequently generated using parallel solution-phase synthesis and Ghosez's reagent. The chemical structures of all semi-synthetic analogues (2-12) were elucidated following analysis of the NMR, MS, UV and IR data. The structures of compounds 8 and 11 were also confirmed by X-ray crystallographic analysis. All library members were evaluated for their ability to inhibit the release of IL-8 and TNF-α. Six analogues showed moderate activity in the IL-8 assay with IC50 values of 2.8-8.3μM, while none of the tested compounds showed any significant effect on inhibiting TNF-α release.

The volatile constituents from then-hexane extracts of the roots and rhizomes ofValeriana officinalis(VO) andValeriana turkestanica(VT) were investigated by GC-MS analysis. Two VO samples were obtained from cultivation, one from commercially available material, while VT was collected in a mountain of Kazakhstan. The most characteristic components present in all of the analysed samples were sesquiterpenoids. The three investigated samples of VO produced mainly valerenane and kessane sesquiterpenoids. Acetoxyvalerenic acid (33.94%), valerenic acid (15.05%), valerenal (11.93%), valeric acid 2,6-dimethylnon-1-en-3-yn-5-yl ester (5.24%), valerenol (3.31%), elemol (3.19%) and (E)-valerenyl isovalerate (2.53%), were the common components identified in then-hexane extract from the roots of VT. In comparison to VO this species does not produce kessane sesquiterpenoids and polyunsaturated fatty acids. This study shows that the roots of VT possess compounds of high biological significance, since they have the appropriate contents of valerenic acid and its derivatives, thus VT can be considered as a substitute for VO.

The aim of this study was to investigate the sleep-promoting effect of a Valerian/Hops mixture in fruit flies. The HPLC analysis showed that Valerenic acid (1260.53 µg/g of extract) and Xanthohumol (Cascade: 827.49 µg/g, Hallertau: 763.60 µg/g, Saaz: 186.93 µg/g) were contained in Valerian and Hop, respectively. The sleep patterns of fruit flies on the Valerian/Hops were examined in both baseline and caffeine-treated conditions. Total activities of flies significantly decreased in 20 mg/mL Valerian (74%), 10 mg/mL Cascade (25%), and 5 mg/mL Hallertau (11%) during nighttime or daytime compared with the control. Valerian/Cascade mixture showed longer sleeping time (ca. 20%) than control group. This mixture-mediated effect was partly observed in caffeine-treated flies. Valerian/Cascade mixture upregulated mRNA expressions of gamma-aminobutyric acid (GABA) receptors and serotonin receptor, and GABA receptors were more strongly regulated than serotonin receptor. In competitive GABA receptor binding assay, Valerian/Cascade mixture extract showed a higher binding ability on GABA receptor than Valerenic acid or/and Xanthohumol which are estimated to be active compounds in the extract. This study demonstrates that a Valerian/Cascade mixture extract improves sleep-related behaviors, including sleeping time, by modulating GABAergic/serotonergic signaling.

A fluorometric imaging plate reader (FLIPR) assay utilizing Chinese hamster ovary (CHO) cells stably transfected with GABAA receptors of α 1 β 2 γ 2 subunit composition was evaluated and validated for rapid screening of plant extract libraries and efficient localization of active compounds in extracts. Validation was performed with pure compounds and extracts known to contain allosteric GABAA receptor modulators. Plants extracts that had been previously reported as active in an assay using Xenopus laevis oocytes transiently expressing GABAA receptors of α 1 β 2 γ 2 subunit composition were also active in the FLIPR assay. A protocol for HPLC-based activity profiling was developed, whereby separations of 0.4 – 1.2 mg of extracts on an analytical HPLC column were found to be sufficient for the sensitivity of the bioassay. The protocol successfully localized the activity of known GABAergic natural products, such as magnolol in Magnolia officinalis, valerenic acid in Valeriana officinalis, and piperine in Piper nigrum extract. EC50 values of compounds (magnolol: 4.81 ± 1.0 µM, valerenic acid: 12.56 ± 1.2 µM, and piperine: 5.76 ± 0.7 µM) were found to be comparable or lower than those reported using Xenopus oocyte assays.

Subunit-selective modulation of γ-aminobutyric acid type A receptors (GABAAR) is considered to exert fewer side effects compared to unselective clinically used drugs. Here, the β2/3 subunit-selective GABAAR modulators valerenic acid (VA) and loreclezole (LOR) guided the synthesis of novel subunit-selective ligands with simplified structures. We studied their effects on GABAARs expressed in Xenopus laevis oocytes using two-microelectrode voltage clamp technique. Five compounds showed significantly more efficacious modulation of GABA-evoked currents than VA and LOR with retained potency and selectivity. Compound 18 [(E)-2–Cyano-3-(2,4-dichlorophenyl)but-2-enamide] induced the highest maximal modulation of GABA-induced chloride currents (Emax: 3114 ± 242%), while 12 [(Z)-3-(2,4-dichlorophenyl)but-2-enenitrile] displayed the highest potency (EC50: 13 ± 2 μM). Furthermore, in hippocampal neurons 12 facilitated phasic and tonic GABAergic inhibition, and in vivo studies revealed significantly more potent protect...

Valeriana wallichii DC., Caprifoliaceae, is used to have anti-ulcer, anti-spasmodic, anti-epileptic, memory enhancer, anti-anxiety, anti-rheumatic, sedative, anti-asthmatic and diuretic activities. V. wallichii is reported to contain valpotriates, valeric acid, valerenic acid, valechlorine, valerianine, resins and alkaloids. Valeric acid, found in V. wallichii appears similar in structure to the neurotransmitter GABA. Valeric acid also acts as an NMDA-receptor antagonist. The aim of present study was to investigate the neuroprotective effect of V. wallichii containing valeric acid and its possible mechanism of action in amelioration of intracerebroventricular streptozotocin induced neurodegeneration in Wistar rats. The rhizomes of V. wallichii were powdered coarsely and extracted by percolation method using dichloromethane. Wistar rats (220⿿250 g) of either sex were divided into 5 groups, comprising 6 animals each. Valeric acid was isolated from plant extract and characterized using FT-IR. Picrotoxin (2 mg/kg) was used as GABA-A antagonist. Intracerebroventricular streptozotocin administration caused significant (p

INTRODUCTION: The availability of herbal medicines over-the-counter (OTC) has increased the use of natural products for self-treatment. Valerian has been used to effectively treat generalized anxiety disorder and insomnia. Studies suggest that valerenic acid may increase gamma-aminobutyric acid (GABA) modulation in the brain. Benzodiazepines have a similar mechanism of action and have been linked to an increased risk of hospitalizations due to traffic accidents. Despite the risk of somnolence, the safety of driving while under the influence of valerian remains unknown. PURPOSE: The purpose of the study was to determine the effects of a one-time valerian 1600mg dose on subjective sedation effects, standardized field sobriety testing (SFST) and driving simulator performance parameters. METHODS: The study design was a randomized, placebo-controlled, double-blind, cross-over trial. For each session, participants received either a dose of valerian or placebo. The outcome measures included a simple visual reaction test (SVRT), subjective sleepiness scales, SFST performance scores, and driving simulator performance parameters. RESULTS: There were no significant differences in the SVRT or sleepiness scales between placebo and valerian exposures, but the study may have been underpowered. SFST total and individual test failure rates were not significantly different between the two exposures. The driving simulator performance parameters were equivalent between the two exposure conditions. CONCLUSIONS: A one-time valerian 1600mg dose, often used to treat insomnia, does not appear to impair driving simulator performance after acute ingestion.Copyright © 2016 Elsevier Ltd. All rights reserved. Language: en

Sumatriptan, dihydroergotamine and methysergide inhibit 1% formalin-induced nociception by activation of peripheral 5-HT1B/1D receptors. This study set out to investigate the pharmacological profile of the antinociception produced by intrathecal and intraplantar administration of ergotamine (a 5-HT1B/1D and 5-HT5A/5B receptor agonist) and valerenic acid (a partial agonist at 5-HT5A receptors). Intraplantar injection of 1% formalin in the right hind paw resulted in spontaneous flinching behavior of the injected hindpaw of female Wistar rats. Intrathecal ergotamine (15nmol) or valerenic acid (1 nmol) blocked in a dose dependent manner formalin-induced nociception. The antinociception by intrathecal ergotamine (15nmol) or valerenic acid (1nmol) was partly or completely blocked by intrathecal administration of the antagonists: (i) methiothepin (non-selective 5-HT5A/5B; 0.01-0.1nmol); (ii) SB-699551 (selective 5-HT5A; up to 10nmol); (iii) anti-5-HT5A antibody; (iv) SB-224289 (selective 5-HT1B; 0.1-1nmol); or (v) BRL-15572 (selective 5-HT1D; 0.1-1nmol). Likewise, antinociception by intraplantar ergotamine (15nmol) and valerenic acid (10nmol) was: (i) partially blocked by methiothepin (1nmol), SB-699551 (10nmol) or SB-224289 (1nmol); and (ii) abolished by BRL-15572 (1nmol). The above doses of antagonists (which did not affect per se the formalin-induced nociception) were high enough to completely block their respective receptors. Our results suggest that ergotamine and valerenic acid produce antinociception via 5-HT5A and 5-HT1B/1D receptors located at both spinal and peripheral sites. This provides new evidence for understanding the modulation of nociceptive pathways in inflammatory pain.

The medicinal properties of Valerian (Valeriana officinalis) root preparations are attributed to the anxiolytic sesquiterpenoid valerenic acid and its biosynthetic precursors valerenal and valerenadiene, as well as the anti-inflammatory sesquiterpenoid β-caryophyllene. In order to study and engineer the biosynthesis of these pharmacologically active metabolites, a binary vector co-transformation system was developed for V. officinalis hairy roots. The relative expression levels and jasmonate-inducibility of a number of genes associated with sesquiterpenoid metabolism were profiled in roots: farnesyl pyrophosphate synthase (VoFPS), valerendiene synthase (VoVDS), germacrene C synthase (VoGCS), and a cytochrome P450 (CYP71D442) putatively associated with terpene metabolism based on sequence homology. Recombinant hairy root lines overexpressing VoFPS or VoVDS were generated and compared to control cultures. Overexpression of the VoFPS cDNA increased levels of the corresponding transcript 4- to 8-fold and sesquiterpene hydrocarbon accumulation by 1.5- to 4-fold. Overexpression of the VoVDS cDNA increased the corresponding transcript levels 5- to 9-fold and markedly increased yields of the oxygenated sesquiterpenoids valerenic acid and valerenal. Our findings suggest that the availability of cytoplasmic farnesyl diphosphate and valerenadiene are potential bottlenecks in Valeriana-specific sesquiterpenoid biosynthesis, which is also subject to regulation by methyl jasmonate elicitation.

In a previous study, we demonstrated that a Valeriana officinalis extract could attenuate increases in serum corticosterone levels in a mouse model of physical and psychological stress. In addition, our results showed that the extract could modulate serotonin (5-HT) and norepinephrine (NE) turnover in the hippocampus and amygdala region. In this study, we intended to investigate the effects of valerenic acid (VA), the main component of V. officinalis extract, on corticosterone levels in serum in normal mice and monoamine turnover in hippocampus-amygdala homogenates in a mouse model of physical and psychological stress. To determine the minimum dose of VA for antianxiety effect, eight-week-old ICR mice were orally administered VA (0.2, 0.5, and 1.0 mg/kg/0.3 mL) once daily for 3 weeks to probe for immobility time and serum corticosterone levels. At a VA dose of 0.5 and 1.0 mg/kg, animals showed a decrease in the duration of immobility time and serum corticosterone levels. To confirm the antianxiety effect of VA, eight-week-old ICR mice received VA at a dose of 0.5 mg/kg, orally, once daily for 3 weeks, before being subjected to physical or psychological stress for 3 days, in a specially designed communication box, followed by estimation of levels of monoamines and their metabolites in the hippocampus-amygdala region. In conclusion, VA administration at 0.5 mg/kg can mitigate the physical and psychological stress response by decreasing the turnover of 5-HT to 5-hydroxyindoleacetic acid and NE to 3-methoxy-4-hydroxyphenylethyleneglycol sulfate in the hippocampus and amygdala.

There is growing interest for medicinal plants in the world drug market. Particularly, Matricaria recutita L., Valeriana officinalis L., Tilia spp., and Camellia sinensis (L.) Kuntze are some of the most consumed medicinal plants for treatment of minor health problems. Medicinal plants are seen as natural and safe, however, they can cause interactions and produce adverse reactions. Moreover, there is lack of consensus in medicinal plants regulation worldwide. DNA barcoding and UHPLC-MS technique are increasingly used to correctly identify medicinal plants and guarantee their quality and therapeutic safety. We analyzed 33 samples of valerian, linden, tea, and chamomile acquired in pharmacies, supermarkets, and herbal shops by DNA barcoding and UHPLC-MS. DNA barcoding, using matk as a barcode marker, revealed that CH1 sold as Camellia sinensis was Blepharocalyx tweediei, and sample TS2 sold as linden belong to Malvales. On the other hand, UHPLC-MS analysis revealed the presence of bioactive compounds (apigenin-7-glucoside, acetoxy valerenic acid, valerenic acid, epigallocatechin, and tiliroside). However, none of samples met minimum content of these active principles (except for valerenic acid in VF3) according to the European Medicines Agency (EMA) and Real Spanish Pharmacopeia. In conclusion, this study revealed the need to incorporate DNA barcoding and HPLC-MS techniques in quality controls of medicinal plants.

Valerian (Valeriana officinalis L.), which is considered as a medicinal plant, is commonly used in traditional medicine. This study aimed to evaluate the effect of arbuscular mycorrhizal (AM) fungi association under moderate and high salinity stress on growth and physio-biochemical traits of V. officinalis. The bio-ameliorative efficiency of two AM species, Rhizophagus intraradices and Funneliformis mosseae was also compared. The mycorrhizal inoculation generally increased the salt tolerance of plant and positively affected plant growth, P, K+, Mg2+ concentration and the ratios of total chlorophyll: carotenoids, K+: Na+, Ca2+: Na+, and Mg2+: Na+ in shoots compared with those of the non-mycorrhizal plants under saline condition. Moreover, the presence of AM symbiosis mitigated the salinity-induced increase in shoot Na+ concentration, shoot proline, and oxidative damage to membranes. AM fungi considerably promoted root proline and total soluble sugars and total phenolics in shoots and roots versus non-mycorrhizal V. officinalis. Moderate salinity stress increased valerenic acid production, which was more pronounced in F. mosseae inoculated plants. The outcome of the symbiosis was associated with the AM species used, and F. mosseae was more efficient than R. intraradices in the alleviation of salinity stress. This study suggests the potential use of mycorrhizal technology as a practical biotechnological approach to enhance growth and augment bioactive compounds production of V. officinalis in salt-affected soils.

Natural products (NPs) are progressively recognized as invaluable source of pharmacological tools and lead structures. To enable NP-inspired retinoid X receptor (RXR) modulator design, three novel RXR-targeting NPs were computationally identified. Among them, valerenic acid was found to be selective for RXRβ, rendering it a unique pharmacological tool compound. The NPs then served as templates for automated, ligand-based de novo design of innovative, easily accessible mimetics that inherited the biological activities of their natural templates.

The roots of Valeriana officinalis L. (Valerianaceae) are used for treating sleep disorders and/or mild nerve tension. The effect of valerenic acid on brain-derived neurotrophic factor (BDNF) has not yet been studied, although it is known that gamma-amino butyric acid A (GABAA) receptor is regulated by BDNF, which modulates the depressive-like behavior and neurogenesis. The purpose of this study is to determine the effect of V. officinalis root extract (VO), its main constituents valerenic acid (VA) and acetoxy valerenic acid (AVA) as well as valerenic acid-free (VAF), acetoxy valerenic acid-free (AVAF) extracts and increasing amounts of valerenic acid containing extracts on the BDNF expression in SH-SY5Y cell lines. The effect of methanolic extracts of VO, VA, AVA, VAF, AVAF, and the extracts whose amount of VA were increased gradually, were tested using a Human BDNF ELISA kit with 17β-estradiol as a positive control. The VO and VA extracts caused a significant (p

Valeriana officinalis (Valerian) root extracts have been used by European and Asian cultures for millennia for their anxiolytic and sedative properties. However, the efficacy of these extracts suffers from variable yields and composition, making these extracts a prime candidate for microbial production. Recently, valerenic acid, a C15 sesquiterpenoid, was identified as the active compound that modulates the GABAA channel. Although the first committed step, valerena-4,7(11)-diene synthase, has been identified and described, the complete valerenic acid biosynthetic pathway remains to be elucidated. Sequence homology and tissue-specific expression profiles of V. officinalis putative P450s led to the discovery of a V. officinalis valerena-4,7(11)-diene oxidase, VoCYP71DJ1, which required coexpression with a V. officinalis alcohol dehydrogenase and aldehyde dehydrogenase to complete valerenic acid biosynthesis in yeast. Further, we demonstrated the stable integration of all pathway enzymes in yeast, resulting in the production of 140 mg/L of valerena-4,7(11)-diene and 4 mg/L of valerenic acid in milliliter plates. These findings showcase Saccharomyces cerevisiae's potential as an expression platform for facilitating multiply-oxidized medicinal terpenoid pathway discovery, possibly paving the way for scale up and FDA approval of valerenic acid and other active compounds from plant-derived herbal medicines.

The aim of this study was to investigate the beneficial effect of Valerian/Cascade mixture on sleeping in mammal models. In pentobarbital-induced sleep model, Valerian, Cascade, and Valerian/Cascade mixture significantly reduced the latency time for sleeping, and total sleeping time effectively increased in these sample groups compared with the control. Valerian/Cascade mixture increased sleep duration by 37%. The mixture significantly increased the non-rapid eye movement (NREM) sleep time by 53% compared with the control, while REM sleeping time was decreased by 33% with Valerian/Cascade mixture, in Electroencephalography (EEG) analysis, resulting in the increase of total sleep time and the decrease of awakening. This sleep-promoting effect was obvious in caffeine-induced awakening model; Valerian, Cascade, and the mixture significantly enhanced NREM and total sleep time, which were reduced by caffeine. Caffeine-induced increase of awakening was effectively deceased to the normal level by these three samples. In particular, delta wave responsible for deep sleep in NREM was greatly increased by the mixture in both normal and caffeine-induced awake models. This sleep-promoting effect of Valerian/Cascade mixture was shown to be due to the upregulation of gamma-aminobutyric acid A receptor (GABAAR). Valerian/Cascade mixture showed 91% binding capacity to GABAA-BZD receptor. Two compounds, Valerenic acid and Xanthohumol, were shown to significantly contribute to the binding activity of Valerian/Cascade mixture on the GABA receptor.

Valeriana officinalis is a medicinal herb which produces a suite of compounds in its root tissue useful for treatment of anxiety and insomnia. The sesquiterpene components of the root extract, valerenic acid and valerena-1,10-diene, are thought to contribute to most of the observed anxiolytic of Valerian root preparations. However, valerenic acid and its biosynthetic intermediates are only produced in low quantities in the roots of V. officinalis. Thus, in this report, Escherichia coli was metabolically engineered to produce substantial quantities of valerena-1,10-diene in shake flask fermentations with decane overlay. Expression of the wildtype valerenadiene synthase gene (pZE-wvds) resulted in production of 12 μg/mL in LB cultures using endogenous FPP metabolism. Expression of a codon-optimized version of the valerenadiene synthase gene (pZE-cvds) resulted in 3-fold higher titers of valerenadiene (32 μg/mL). Co-expression of pZE-cvds with an engineered methyl erythritol phosphate (MEP) pathway improved valerenadiene titers 65-fold to 2.09 mg/L valerenadiene. Optimization of the fermentation medium to include glycerol supplementation enhanced yields by another 5.5-fold (11.0 mg/L valerenadiene). The highest production of valerenadiene resulted from engineering the codon-optimized valerenadiene synthase gene under strong Ptrc and PT7 promoters and via co-expression of an exogenous mevalonate (MVA) pathway. These efforts resulted in an E. coli production strain that produced 62.0 mg/L valerenadiene (19.4 mg/L/OD600 specific productivity). This E. coli production platform will serve as the foundation for the synthesis of novel valerenic acid analogues potentially useful for the treatment of anxiety disorders.

Ferula sumbul (Umbelliferae) roots have a characteristic musk odour and it has been traditionally used for relieving anxiety, as a sedative in hysteria and other nervous disorders. Present investigation aims to develop and validate a simple, robust, accurate and fast analytical ultra-performance liquid chromatography technique for the estimation of valerenic acid in F. sumbul roots. F. sumbul root extract was prepared by refluxing the powdered roots with methanol for 30 minutes. A simple method for the estimation of valerenic acid has been developed and validated using ultra-performance liquid chromatography with photodiode array detector. The estimation was achieved using BEH Shield RP, C-18 column (2.1×50 mm, 1.7 μm) with isocratic elution of methanol and 0.5% phosphoric acid (75:25) at a flow rate of 0.25 ml/min and detection at 218 nm. The method has been developed for the first time and is accurate with good linearity (r2>0.998). F. sumbul roots were found to contain 12.62±0.074 µg/g valerenic acid. The developed method can be selectively used for the estimation of valerenic acid in the roots of F. sumbul. All the validation parameters were found to be within the permissible limits prescribed by ICH guidelines.

Valerenic acid (VA) is a pharmacologically-active sesquiterpene found in valerian (Valeriana officinalis L., Valerianaceae) roots and rhizomes. The plant produces only small amounts of this metabolite naturally. So, induction of hairy roots as well as elicitation can be useful to increase its commercial production. In this study, Wild-type strain ‘A13’ of Agrobacterium rhizogenes was used to induce hairy roots in valerian. The influence of three different elicitors including Fusarium graminearum extract (FE), methyl jasmonate (MJ) and salicylic acid (SA) on VA production in the selected hairy root line ‘LeVa-C4’ was also investigated. The 23-day-old cultures were treated with different concentrations of the elicitors at exposure time of 3 and 7 days. FE (1%) and MJ (100 µM L−1) highly promoted VA production at 7 days after elicitation, to a level of 12.31- and 6-fold higher than that of non-elicited controls, respectively, and FE did not exert any negative effects on biomass yield of hairy root. SA did not significantly increase the production of VA. This is the first time study to assess the elicitation of hairy root cultures to promote VA biosynthesis in valerian and the resulting experiments demonstrated that F. graminearum extract and MJ were indeed a potent inducer of VA biosynthesis.

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.

Valeriana officinalis is used in herbal medicine of many cultures as mild sedatives and tranquilizers. In this study, we investigated the effects of extract from valerian root extracts and its major component, valerenic acid on memory function, cell proliferation, neuroblast differentiation, serum corticosterone, and lipid peroxidation in adult and aged mice. For the aging model, D-galactose (100 mg/kg) was administered subcutaneously to 6-week-old male mice for 10 weeks. At 13 weeks of age, valerian root extracts (100 mg/kg) or valerenic acid (340 μg/kg) was administered orally to control and D-galactose-treated mice for 3 weeks. The dosage of valerenic acid (340 μg/kg), which is the active ingredient of valerian root extract, was determined by the content of valerenic acid in valerian root extract (3.401±0.066 mg/g) measured by HPLC. The administration of valerian root extract and valerenic acid significantly improved the preferential exploration of new objects in novel object recognition test and the escape latency, swimming speeds, platform crossings, and spatial preference for the target quadrant in Morris water maze test compared to the D-galactose-treated mice. Cell proliferation and neuroblast differentiation were significantly decreased, while serum corticosterone level and lipid peroxidation in hippocampus were significantly increased in the D-galactose-treated group compared to that in the control group. The administration of valerian root extract significantly ameliorated these changes in the dentate gyrus of both control and D-galactose-treated groups. In addition, valerenic acid also mitigated the D-galactose-induced reduction of these changes. These results indicate that valerian root extract and valerenic acid enhance cognitive function, promote cell proliferation and neuroblast differentiation, and reduce serum corticosterone and lipid peroxidation in aged mice.

major inhibitory GABA systems are known to take part a vital role in epilepsy, associated with excessive neuronal circuitry excitation. This excitatory action reflects seizures which result from GABA inhibitory circuit dysfunction. GABA mediates its fast inhibition through GABAA receptors by activating it and then opens the chloride channels. This opening allows chloride ions to flow into the interior of the cell which inhibits the excitability. This inhibitory action devises anticonvulsive properties as a consequence. So GABAA receptors are primary targets in the pathophysiology of epilepsy. Enhancement in the the action of GABAA receptors is the basis of epileptic seizures reduction on which many antiseizure drugs act. Modulation of GABAA receptor can be shown by many synthetic and natural compounds. Valerenic acid, a plant origin compound shows modulatory effects on GABAA receptors. In our present study, the homology model of the GABAA receptor subunit beta-3 is build and docking studies are performed with Valerenic acid. Docking analysis is done to know the binding interactions and their binding affinity. The results revealed the interacting amino acids which are involved in binding of GABAA receptor subunit beta-3 with Valerenic acid are ASP35, GLN56, PHE55, TYR120, ARG111 and TYR 54.

Made available in DSpace on 2018-11-26T15:29:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-05-02 Universidade Estadual do Sudoeste da Bahia Pontificia Universidad Javeriana Jovenes Investigadores (Colciencias) Parkinson's disease (PD) is one of the most common neurodegenerative disorders. A theoretical approach of our previous experiments reporting the cytoprotective effects of the Valeriana officinalis compounds extract for PD is suggested. In addiction to considering the PD as a result of mitochondrial metabolic imbalance and oxidative stress, such as in our previous in vitro model of rotenone, in the present manuscript we added a genomic approach to evaluate the possible underlying mechanisms of the effect of the plant extract. Microarray of substantia nigra (SN) genome obtained from Allen Brain Institute was analyzed using gene set enrichment analysis to build a network of hub genes implicated in PD. Proteins transcribed from hub genes and their ligands selected by search ensemble approach algorithm were subjected to molecular docking studies, as well as 20 ns Molecular Dynamics (MD) using a Molecular Mechanic Poison/Boltzman Surface Area (MMPBSA) protocol. Our results bring a new approach to Valeriana officinalis extract, and suggest that hesperidin, and probably linarin are able to relieve effects of oxidative stress during ATP depletion due to its ability to binding SUR1. In addition, the key role of valerenic acid and apigenin is possibly related to prevent cortical hyperexcitation by inducing neuronal cells from SN to release GABA on brain stem. Thus, under hyperexcitability, oxidative stress, asphyxia and/or ATP depletion, Valeriana officinalis may trigger different mechanisms to provide neuronal cell protection. Univ Estadual Sudoeste Bahia, Dept Ciencias Biol, Jequie, Brazil Univ Estadual Sudoeste Bahia, Dept Quim & Exatas, PNPD CAPES, Jequie, Brazil Pontificia Univ Javeriana, Fac Ciencias, Dept Nutr & Bioquim, Bogota, DC, Colombia UBA CONICET, Inst Invest Cardiol Prof Dr Alberto C Taquini INI, Buenos Aires, DF, Argentina Univ Estadual Paulista, Inst Biol, Dept Bioquim, Campinas, SP, Brazil Univ Fed Estadual Feira Santana, Dept Ciencias Biol, Feira De Santana, Brazil Univ Autonoma Chile, Inst Ciencias Biomed, Santiago, Chile Univ Cient Sur, Lima, Peru Univ Estadual Paulista, Inst Biol, Dept Bioquim, Campinas, SP, Brazil Pontificia Universidad Javeriana: 5575 Pontificia Universidad Javeriana: 5024 Jovenes Investigadores (Colciencias): 6027

Valeriana fauriei (V. fauriei), which emits a characteristic and unpleasant odor, is important in traditional medicine. In this study, the expression of terpenoid biosynthetic genes was investigated in different organs that were also screened for volatile compounds including valerenic acid and its derivatives. Specific expression patterns from different parts of V. fauriei were observed using quantitative real-time PCR (qRT-PCR). The highest transcript levels of biosynthetic genes involved in mevalonic acid (MVA) and methylerythritol phosphate (MEP) production were found in the stem. Although the amounts of volatile compounds were varied by organ, most of the volatile terpenoids were accumulated in the root. Gas chromatography mass spectrometry (GC-MS) analysis identified 128 volatile compounds, which represented 65.33% to 95.66% of total volatiles. Certain compounds were only found in specific organs. For example, isovalerenic acid and valerenic acid and its derivatives were restricted to the root. Organs with high transcript levels did not necessarily have high levels of the corresponding chemical constituents. According to these results, we hypothesize that translocation may occur between different organs in V. fauriei.

Valerian is one of the most commonly used herbal remedies for the treatment of insomnia and anxiety. Valerian extracts allosterically modulate GABAA receptors, an action related to valerenic acid, which is one of the active compounds determined from pharmacological studies. Derivatives of valerenic acid, i.e. acetoxy valerenic acid or hydroxy valerenic acid, do not allosterically modulate GABAA receptors, but they bind to identical binding sites. Therefore, the question arises whether they might interfere with the effects of valerenic acid. Two valerian extracts were tested in the elevated plus maze test and the tail suspension test for anxiolytic and antidepressive activity, respectively. Reference substances were diazepam (1.0mg/kg) and imipramine (30mg/kg). The extracts were standardized to the identical total amounts of the acids (0.1; 0.5; 1.0 and 2.0mg/kg), i.e. valerenic and acetoxy valerenic acid, but the ratio between the acids was different (12:1 and 1:1.5). The extract with the ratio 12:1 prolonged the time spent on the open arm significantly when 0.5mg/kg was applied. Of the other extract, with the ratio 1:1.5, four times that amount was required (2.0mg/kg). Both of the tested extracts did not show any antidepressive effect, rather the other way around, the extract with the ratio 1:1.5 prolonged the immobility phase. However, since the core body temperature was reduced by the 1.0 and 2.0mg/kg extract dose, the prolongation may be related to the temperature phenomenon and is not indicative of a specific depressive action. In conclusion, the anxiolytic activity of the valerian extract seems rather related to valerenic acid and, moreover, standardization with respect to the total amount of valerenic acids, i.e. valerenic acid together with acetoxy valerenic acid, is misleading.

Valerian extract is used in complementary and alternative medicine for its anxiolytic and sedative properties. Our previous research demonstrated valerian interactions with glutamate receptors. The purpose of this study was to determine if valerian anxiolytic properties are mediated by metabotropic glutamate receptors (mGluR) such as mGluR (1/5) (mGluR I) and mGluR (2/3) (mGluR II). Adult wild-type zebrafish (Danio rerio) prefer the black compartment and avoid the white compartment in the dark/light preference task. Zebrafish exposed to 1 mg/mL of valerian extract or 0.00117 mg/mL valerenic acid increased their residence time in the white side by 84.61 ± 6.55 % and 58.30 ± 8.97 %, respectively. LAP3 (mGluR I antagonist) and EGLU (mGluR II antagonist) significantly inhibited the effects of valerian and valerenic acid. These results demonstrated that valerian and valerenic acid have anxiolytic properties in the zebrafish. Moreover, the selective interaction of valerian with mGluR I and II represent an alternative explanation for the anxiolytic properties of this plant and support the role of mGluR in anxiety.

Valerian (Valeriana officinalis) is a popular medicinal plant in North America and Europe. Its root extract is commonly used as a mild sedative and anxiolytic. Among dozens of chemical constituents (e.g. alkaloids, iridoids, flavonoids, and terpenoids) found in valerian root, valerena-4,7(11)-diene and valerenic acid (C15 sesquiterpenoid) have been suggested as the active ingredients responsible for the sedative effect. However, the biosynthesis of the valerena-4,7(11)-diene hydrocarbon skeleton in valerian remains unknown to date. To identify the responsible terpene synthase, next-generation sequencing (Roche 454 pyrosequencing) was used to generate ∼ 1 million transcript reads from valerian root. From the assembled transcripts, two sesquiterpene synthases were identified (VoTPS1 and VoTPS2), both of which showed predominant expression patterns in root. Transgenic yeast expressing VoTPS1 and VoTPS2 produced germacrene C/germacrene D and valerena-4,7(11)-diene, respectively, as major terpene products. Purified VoTPS1 and VoTPS2 recombinant enzymes confirmed these activities in vitro, with competent kinetic properties (K(m) of ∼ 10 μm and k(cat) of 0.01 s(-1) for both enzymes). The structure of the valerena-4,7(11)-diene produced from the yeast expressing VoTPS2 was further substantiated by (13) C-NMR and GC-MS in comparison with the synthetic standard. This study demonstrates an integrative approach involving next-generation sequencing and metabolically engineered microbes to expand our knowledge of terpenoid diversity in medicinal plants.

A detailed study of the total synthesis of valerenic acid, a well known GABAA receptor subtype modulator, is described. Both successful as well as unsuccessful attempts towards the synthesis of the title compound are presented, including four different strategies to synthesize one of the key intermediates. The first two strategies are based on epoxides provided from the chiral pool, whereas the last two approaches rest on stereocontrolled modifications of 2-cyclopentenone. The streamlined synthesis implements a new one-pot reaction, which combines the addition of a Grignard species with an acid-catalyzed isomerization of the intermediate allylic alcohol. Further highlights are a stereo- and regioselective hydroxy-directed Diels–Alder reaction, a hydroxy-directed hydrogenation, and a final Negishi coupling reaction. After optimization of our synthesis, the preparation of several easily available derivatives is also discussed. Amides obtained by functionalization of the carboxyl group are more than twice as active as valerenic acid.