Article

The Gamma-Aminobutyric Acidergic Effects of Valerian and Valerenic Acid on Rat Brainstem Neuronal Activity

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Abstract

Unlabelled: Valerian is a medicinal herb that produces anxiolytic and sedative effects. It was suggested that valerian acts via gamma-aminobutyric acid (GABA)ergic mechanisms. Previous studies showed binding of valerian extract to GABA receptors, but the functional effect of the binding has not been demonstrated. In this study we evaluated the GABAergic effect of valerian extract and one of its major constituents, valerenic acid, on brainstem neuronal activity in an in vitro neonatal rat brainstem preparation. We first observed that muscimol, a GABA(A) receptor agonist, decreased the firing rate in most brainstem neurons in a concentration-related fashion; 30 micro M produced a 38.9% +/- 3.0% (mean +/- SE) inhibition compared with control values (P < 0.01; 50% inhibitory concentration [IC(50)], 2.0 +/- 0.1 microM). This effect was antagonized by bicuculline (10 microM), a GABA(A) antagonist. Then we showed that valerian extract 3 mg/mL induced a 29.6% +/- 5.1% inhibition with an IC(50) of 240 +/- 18.7 microg/mL, whereas 100 microM valerenic acid induced a 22.2% +/- 3.4% inhibition with an IC(50) of 23 +/- 2.6 microM (both P < 0.01). Bicuculline antagonized the inhibitory effects of both the valerian extract and valerenic acid. In addition, pretreatment with valerian extract or valerenic acid decreased the brainstem inhibitory effects produced by muscimol (both P < 0.05), suggesting that these compounds play an important role in the regulation of GABAergic activity. Data from this study suggest that the pharmacological effects of valerian extract and valerenic acid are mediated through modulation of GABA(A) receptor function. Thus, valerian may potentiate the sedative effects of anesthetics and other medications that act on GABA receptors, and presurgical valerian use may cause a valerian-anesthetic interaction. Implications: Valerian is an herb used in treating anxiety and insomnia. We observed that the valerian effects are mediated through brain gamma-aminobutyric acid (GABA) receptors in a rat brainstem preparation. Thus, valerian may potentiate the effects of anesthetics that act on GABA receptors, and presurgical valerian use may cause a valerian-anesthetic interaction.

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... Various CNS receptors have been identified to be involved in the overall pharmacological activity of valerian extracts, including adenosine-, benzodiazepine-, serotonin and GABA-receptors [60,72,[85][86][87] but, depending on the preparation of the extracts, their effects are markedly affected. In fact, most of these studies relate this herb to the inhibitory neurotransmitter GABA [88] or its receptors [49,56,57], but until now all constituents responsible for the GABA-mediated activity of valerian remain unclear. It was demonstrated that GABA A receptor is modulated by valerenic acid [50] and derivatives, which cross the BBB, through an unidentified transport system, and interact with these receptors within the brain [71]. ...
... Also, in a study using valerian extract and valerenic acid in neonatal rat brainstem preparations, a modulation of GABA A receptor function on the neuronal activity of this region was shown. This allowed concluding that it may potentiate the sedative effects of anesthetics and other medications that act on these receptors and may cause a valerian-anesthetic interaction presurgically [49]. Additionally, showed that the aqueous valerian extract inhibited [3H] GABA uptake and induced the Ca 2+independent release of [3H] GABA [57,91]. ...
Article
Background Valerian extract is widely used in dietary supplements as well as in conventional, traditional and alternative medicines. It is one of the most used herbal plants for the treatment of several disorders, mainly related to the digestive and the nervous systems. Dozens of chemical constituents with pharmacological and therapeutic properties were identified in essential oils and/or other extracts of valerian’s roots, rhizomes and aerial parts. This review summarizes and updates the current knowledge about the pharmacological properties of valerian, highlighting the most recent clinical, in vitro and in vivo findings, and intends to identify and propose future directions for further research regarding the effective biological effects of Valeriana spp. Methods This review analyzed the scientific literature published in PubMed, Science Direct and Web of Science. Results Some reports are contradictory or inconclusive, probably due to the presence of chemically distinct chemotypes within a species of Valeriana or to different approaches adopted in different studies. Also, there are a number of studies showing that co-administration of herbal supplements and drugs may promote pharmacokinetic and pharmacodynamic herb-drug interactions. Conclusion It is of utmost importance to clarify the state of the art related to Valeriana spp. therapeutic properties and their effects on metabolism.
... Valeriana officinalis has been used as a sedative and to treat anxiety and sleep disorders (9,10). Various effects of V. officinalis have been reported; it has been suggested that Valeriana exerts its effects through gamma-aminobutyric acid (GABA) ergic mechanisms (11). In a previous study, V. officinalis exerted antioxidant effects and decreased lipid peroxidation induced by quinolinic acid (12). ...
... Additionally, valerian root extract has been proven to exert neuroprotective effects in several neurodegenerative diseases, such as Parkinson's and Alzheimer's disease (13)(14)(15). It has also been reported that the effects of valerian and its active component valerenic acid are closely related to the GABA system (11,48). GABA-induced depolarization activates cAMP response element-binding signaling, which promotes neuronal survival by activating downstream survival genes (49). ...
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Exposing a pregnant female to stress is a risk factor for the development of psychiatric disorders in the offspring. In the present study, we examined the effects of an extract of Valeriana fauriei (VF) root (100 mg/kg/day, administered on postnatal days 35-56) on behavioral patterns as well as protein expression in the prefrontal cortex of the offspring of prenatally-stressed rats. Modified behavioral tests, including the forced swim test, the open field test, a social interaction test and the prepulse inhibition test were performed and many of the parameters were found to decrease in the offspring of the rats exposed to PNS compared with the offspring of the non-stressed rats. Western blot and immunohistochemical analyses of the prefrontal cortex revealed that the downregulation of several neurodevelopmental proteins in the offspring of rats dams exposed to PNS was reversed after treatment with VF extract. These findings demonstrate that the downregulation of several proteins in the prefrontal cortex of the offspring of prenatally‑stressed rats may be associated with subsequent behavioral changes, and that these phenomena recovered following VF treatment. Our results suggest that VF decreases the incidence of prenatal stress related-psychiatric disorders, such as depression and schizophrenia.
... Case reports indicate there may be possible interaction with the antidiarrhoeal drug loperamide (Imodium) and the herbal medicines ginkgo and St. John's Wort (Williamson et al. 2013). Valerian may potentiate the effects of anaesthetics that act on GABA receptors, thus valerian should be avoided pre-surgery to avoid a potential valerian-anaesthetic interaction (Yuan et al. 2004). There have been no clinical reports involving interactions with other sedatives. ...
Chapter
This chapter presents indications, clinical evidence, pre-clinical evidence, mechanisms of action, interactions, and contraindications of valerian (Valeriana officinalis L.). Valerian is used as a mild sedative to treat symptoms of anxiety, stress and insomnia, including (and especially) during menopause. The chemical composition of V. officinalis varies considerably, depending on subspecies or variety, growing conditions and age or type of extract. Significant constituents include the volatile oil, which contains bornyl acetate and bornyl isovalerate, β-carophyllene, valeranone, valerenic acid and other sesquiterpenoids and monoterpenes, iridoids (valepotriates), alkaloids, sterols and amino acids. Adverse effects, dosage, and general plant information are included in the chapter. Valerian was used to alleviate stress caused by air raids in the First World War.
... Similarly, an animal study showed that valerian extract was more effective than diazepam to alleviate anxiety in rats (39). The valerenic acid component of valerian is supposed to imitate the activities of GABA (40). ...
... Nervous tissue is composed of two types of cells: neurons responsible for receiving, transmitting and processing the message and release neurotransmitter and neuroglia responsible for nutrition, protection and supporting nerve cells, including astrocytes, oligodendrocytes, microglia and ependymal [12,13]. Astrocyte have important role in neurometabolism, maintaining consistency and rigidity of the nervous system, mediator uptake and prevention of electrical spreading and protection of brain and spinal cord from injury [14,15]. ...
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Introduction: The valerian root extract has been used to treat sleep disorders, stress, depression, anxiety, muscle stiffness and tension. Astrocyte cells are involved in neural support, nutrition and protection. They regulate the transmission of electrical impulses within the brain. Aim: The aim of the present study was to evaluate the effect(s) of valerian extract on the number and size of the astrocyte cells in raphe magnus nucleus of rats. Materials and Methods: In the present experimental study, 40 male Wistar rats weighing 170-250 gm were randomly divided into four groups as follows: one control and three experimental groups. The control group received distilled water while animals in Group 2, 3 and 4 were gavaged by 300, 400 and 600 mg valerian root extract daily, respectively for two weeks. Astrocyte cells were stained with phosphotungstic acid. The size and number of astrocyte cells were calculated using the LS starter software. The collected data were analysed using SPSS statistical analysis with ANOVA and LSD tests. results: The mean number of astrocytes in experimental Groups 3 and 4 showed a signifcant increase in comparison with the control and experimental Group 2 (p<0.05). The mean diameter of astrocytes in all groups compared with the control group showed a signifcant decrease. Moreover, in Group 2, compared with Groups 3 and 4, the difference was statistically signifcant (p<0.05). conclusion: Aqueous extracts of valerian taken orally will increase the number of astrocytes in the raphe magnus. In addition, administration of this extract reduced the diameter of astrocytes in nucleus raphe magnus, which is indicative of cell proliferation in the nucleus raphe magnus
... Valerian extract and the constituent valerenic acid have been shown to modulate the GABA A receptor. Yuan et al. (19) reported that valerian extracts bound to the GABA receptor in vitro, and Dietz et al. (20) also reported another mechanism of sleep. Valerian extracts had high binding affinity for the 5-HT5A receptor. ...
Article
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We evaluated the sleep enhancement activity of the medicinal herbs valerian (Valeriana officinalis), jujube (Ziziphus jujube), lotus seed (Nelumbo nucifera), Gastrodia elata, Polygonatum sibiricum, and baekbokryung (Poria cocos), which can relieve insomnia in a Drosophila model. Locomotor activity was measured in the Drosophila model to evaluate the sleep activity of Korean medicinal herbs traditionally used as sleep aids. The group treated with lotus seed extract showed less nocturnal activity. Treatment with 10 or 20 mg/mL of P. sibiricum significantly reduced nocturnal activity compared to the control group (P<0.05). The activity and sleep bouts of fruit flies were significantly decreased by a high-dose treatment (10 mg/mL) of lotus or P. sibiricum extracts at night. Caffeine-treated Drosophila showed increased nocturnal activity and decreased total sleep time (P<0.05). Flies receiving the 10 mg-doses of lotus seed or P. sibiricum extract showed significantly different nocturnal locomotor activity and total sleep time compared to caffeine-treated Drosophila. Lotus seed and P. sibiricum extracts are attractive and valuable sleep-potentiating nutraceuticals.
... Valerian is a positive GABA A receptor modulator acting in a dose-dependent manner on a site other than the GABA binding site (Yuan et al., 2004) and increases GABA A neurotransmission (Cavadas et al., 1995). This effect is verified with the demonstration that valerenic acid binds to the β3 subunit of the GABA receptor (Khom et al., 2007). ...
Article
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The rapid iterative negative geotaxis (RING) assay is a commonly used behavioral test in Drosophila based on digital imaging of flies and requires minimal equipment and space. Larval mobility can be used to reliably determine the effect of drugs on locomotion in Drosophila larvae. The effects of Valeriana officinalis extract (VoE) and melatonin (ME) were tested in Drosophila melanogaster flies and larvae. In the RING assay, the locomotor activity of flies was reduced to 30.6, 72 and 70.4% when exposed to 10 mg/ml VoE, 8 mM ME, and a combination of 8 mM ME + 10 mg/ml VoE, respectively. The performance index (PI) was reduced to 68.9% (P = 0.0058), 33.3% (P = 0.0001), and 70% (P = 0.0013) when flies were exposed to 8 mM ME, 10 mg/ml VoE, and a combination of 8 mM ME + 10 mg/ml VoE, respectively. The number of body wall contractions of Drosophila larvae (nBWC) was reduced to 47.8, 37.7 and 38.5% when larvae were exposed to 8 mM ME, 10 mg/ml VoE, and a combination of 8 mM ME + 10 mg/ml VoE, respectively. The displacement velocity (V 0) of larvae decreased significantly to 67.6, 60.1 and 55.6% when larvae were exposed to 8 mM ME, 10 mg/ml VoE, and a combination of 10 mg/ml VoE + 8 mM ME, respectively (P < 0.05). The effects of the VoE extract were not synergistic with ME as demonstrated by the RING assay, nBWC, and V 0. Based on these results, valerian root extracts have demonstrated sedative effects that are better than those of melatonin in fruit flies, but did not show any increase in sedative effect when combined with melatonin.
... These results indicate that chamomile inclusion in quail diets during the laying period has a positive effect on bird welfare due to the modulation of stress-related behaviors (Nääs et al., 2010). The anxiolytic properties of chamomile that provide sedative and calming effects (Yuan et al., 2004) may have contributed to these results. ...
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ABSTRACT The objective of this study was to evaluate the effect of chamomile extract on Japanese quail on their performance, animal behavior, tonic immobility, body injuries, and surface temperature. The trial was conducted using 108 quail distributed in a completely randomized experimental design, with three treatments (0, 2.5, and 5.0 g chamomile/kg of feed), six replicates, and six birds per treatment, evaluated in six measures repeated in time (14, 28, 42, 56, 70, and 84 days of trial). The inclusion of chamomile presented a quadratic effect on sitting behavior, estimating the inclusion of 1.8 g chamomile/kg to maximize this behavior. There was a decreasing linear effect for aggressive pecking, that is, the higher the inclusion of chamomile in the diet, the lower the expression of this behavior. The inclusion of 1.8-5.0 g chamomile/kg in a Japanese quail diet reduces the behavior of aggressive pecking, in addition to keeping the birds seated longer. These results are innovative because they show in the literature for the first time that chamomile supplemented in Japanese quail diets has the capacity to modulate the behavior of the quail, leading to an improvement in the welfare of quail raised in cages.
... An aqueous extract was shown to increase the release and inhibit the recapture of GABA. 3 V. officinalis was shown to increase GABA levels in rat brain homogenate and hippocampal neuronal cultures. 2,20 Valerenic acid was found to have an inhibitory effect on muscimol-sensitive neurons in vitro via GABA A -receptors 26 ; to be a subunit-specific allosteric modulator of GABA A receptors; and extract fractions with high content of valerenic acid exhibited strong receptor activation. 22 We report here clear evidence for the relaxant effect on skeletal muscle of a standardized extract of V. officinalis, the effect being mild compared to that of tetrazepam. ...
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Valeriana officinalis L. root extracts are traditionally taken for their sedative and anxiolytic properties and are also used for muscle relaxation. Relaxant effects were clearly observed on smooth muscle whereas data on effects on skeletal muscle are scarce and inconsistent. The aim of this study was to assess whether a standardized extract (SE) of V. officinalis had myorelaxant effects by decreasing skeletal muscle strength and/or neuromuscular tone in mice. Mice received an acute dose of V. officinalis SE (2 or 5 g/kg per os) or tetrazepam (10 mg/kg ip), a standard myorelaxant drug. Thirty minutes later, the maximal muscle strength was measured using a grip test, while global skeletal muscle function (endurance and neuromuscular tone) was assessed in a wire hanging test. Compared to tetrazepam, both doses of V. officinalis SE induced a pronounced decrease in skeletal muscle strength without any significant effects on endurance and neuromuscular tone. This study provides clear evidence that the extract of V. officinalis tested has a relaxant effect on skeletal muscle. By decreasing skeletal muscle strength without impacting endurance and neuromuscular tone, V. officinalis SE could induce less undesirable side effects than standard myorelaxant agents, and be particularly useful for avoiding falls in the elderly. © 2017 Center for Food and Biomolecules, National Taiwan University.
... Thus, the extract of this plant may be a drug target. Some authors point that the use of 1600 mg dose, commonly used to reduce insomnia, does not impair driving simulator performance after acute ingestion of this plant (Thomas et al., 2016;Kessler et al., 2012;2005;Yuan et al.., 2004). Valeric acid and valepotriates present in the roots of VO reduces anxiety and improve the quality of sleep possibly due to relation to Valium receptors in the brain. ...
... Other studies revealed binding of valerian extract to GABA receptors, but the functional effect of the binding was not demonstrated. Data from the study of Yuan et al [37] and Trauner et al [38] suggest that the pharmacological effects of valerian extract and valerenic acid are mediated through modulation of GABAA receptor function. By passive diffusion valerenic acid is known to penetrate into the central nervous system trans cellular. ...
Article
Full-text available
Valerian (Valeriana officinalis) belonging to valerianaceae family is a well known herb and medicinal plant that has been widely used all over the world especially in Europe, China and Middle East. It is widely used as a sleep aid and sedative in many parts of the world but is also known to relax smooth muscle, hence used for treating stomach and intestine cramps. Alkaloids, terpenes, organic acids and its derivatives, valepotriates and flavones are the known pharmacologically active compounds found in valerian extract. In general, it is accepted that the valepotriates are the compounds responsible for the sedative activity of the Valerianaceae. The present article aims at reviewing the recent reports on its constituents, traditional use, clinical use and scientific verification of pharmacological actions of valerian.
... Valerenic acid (VA), which has a sesquiterpene carboxylic acid skeleton isolated from Valeriana officinalis, is regarded as the major active compound. The anxiolytic potential of VA has been demonstrated with in vitro and in vivo experiments (Yuan et al., 2004;Khom et al., 2007;Sichardt et al., 2007;Trauner et al., 2008;Benke et al., 2009;Khom et al., 2010;Murphy et al., 2010). Studies have shown that VO modulates GABA A receptors due to VA. AVA and hydroxy valerenic acid (HVA) do not modulate GABA A receptors but are linked to the identical binding sites (Felgentreff et al., 2012). ...
Article
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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 < 0.001) increase in the BDNF expression in SH-SY5Y cells compared to control. This effect completely disappeared when cells were treated with VAF extract. AVA alone did not show any significant change in the BDNF levels. The extracts with increasing amount of VA led to a concentration- dependent effect on the cells. In conclusion, our findings suggest that the antidepressant-like effect of the VO extract is also related to BDNF expression, and that this is mainly due to the presence of VA in the extract. Removing VA from VO extract leads to a loss of activity. Moreover, the concentration of VA plays a role for BDNF expressions in SH-SY5Y cells, which demonstrates the importance of quality control on the commercially available products.
... Valepotriates potentiate secretion and block reuptake of the main inhibitory CNS mediator -Gammaaminobutyric acid (GABA) 16 . Valerenic acid modulates GABA A receptors and also supports the anxiolytic action 17 . In our study the individual Valeriana officinalis extract doesn't alter significantly the locomotor activity of rats. ...
Article
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Anxiety is a significant social problem that could deteriorate the quality of life of individuals. It disturbs the normal circadian rhythms, leading to an increase of cardio-vascular diseases and distortions in the functions of the immune system. Antistress I and Antistress II are herbal combinations containing in different proportions dry extracts obtained from Serratula coronata, Hypericum perforatum, Valeriana officinalis, Crataegus monogyna and Melissa officinalis. The present study evaluates the acute toxicity and the anxiolytic effect of these combinations and the individual extracts which they contain after their oral administration to male Wistar rats. Doses of 5g/kg b.w. and 10g/kg b.w. are used for the evaluation of acute toxicity. Assessment of the anxiolytic effect is carried out at three doses – 100, 250 and 500 mg/kg b.w. by using the test-Elevated plus maze. The results about the acute toxicity show a survival rate of 100% for all extracts at a dose up to10g/kg b.w. The evaluation of the anxiolytic effect on an acute stress model in rats demonstrates that both combinations Antistress I and Antistress II possess anxiolytic properties which are significant only at the highest dose. The results also give us the reason to conclude that the effect of Antistress II on anxiety is better compared to Antistress I.
... Several plant compounds have therefore been studied to determine scientifically their mechanism of action. The valerenic acid is responsible for the effects of V. officinalis on GABAARs [36]. However, its site of action remains unknown. ...
Article
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Lemon balm (Melissa officinalis) and valerian (Valeriana officinalis) have been consumed by humans since Antiquity, usually as herbal tea and brewing, for their sedative and relaxing capacities. These properties are associated with empirical observations of the effects of these plants on the body. But since the advent of phytotherapy as alternative medicine, it appeared on the market alcoholic extracts or essential oils, for which the same indications are claimed. It is therefore necessary to clarify or define the mechanisms of action of their various constituents to explain their effectiveness. We review here the current knowledge about the pharmacological properties – particularly the molecular targets – of the bioactive compounds of lemon balm and valerian. In this way, the activities of lemon balm and valerian, empirically observed throughout the body, can be explained and objectified at the molecular and cellular levels thanks to the mode of action of their molecular contents (terpenoids and phenolic derivatives). Our interest is to scientifically explain the pharmacological effects of these two plants in traditional medicine.
... It has been reported that flavonoids and alkaloids are primarily observed in the aerial parts and sesquiterpenes and iridoids noticed in rhizomes and roots [6,7]. Among these constituents, valerenic acid is responsible for the sedative effects and its derivatives are produced in roots and rhizomes as principal compounds of Valeriana species [8,9]. ...
Article
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Background: Valeriana fauriei is commonly used in the treatment of cardiovascular diseases in many countries. Several constituents with various pharmacological properties are present in the roots of Valeriana species. Although many researches on V. fauriei have been done since a long time, further studies in the discipline make a limit due to inadequate genomic information. Hence, Illumina HiSeq 2500 system was conducted to obtain the transcriptome data from shoot and root of V. fauriei. Results: A total of 97,595 unigenes were noticed from 346,771,454 raw reads after preprocessing and assembly. Of these, 47,760 unigens were annotated with Uniprot BLAST hits and mapped to COG, GO and KEGG pathway. Also, 70,013 and 88,827 transcripts were expressed in root and shoot of V. fauriei, respectively. Among the secondary metabolite biosynthesis, terpenoid backbone and phenylpropanoid biosynthesis were large groups, where transcripts was involved. To characterize the molecular basis of terpenoid, carotenoid, and phenylpropanoid biosynthesis, the levels of transcription were determined by qRT-PCR. Also, secondary metabolites content were measured using GC/MS and HPLC analysis for that gene expression correlated with its accumulation respectively between shoot and root of V. fauriei. Conclusions: We have identified the transcriptome using Illumina HiSeq system in shoot and root of V. fauriei. Also, we have demonstrated gene expressions associated with secondary metabolism such as terpenoid, carotenoid, and phenylpropanoid.
... Valerian has been used to treat insomnia and generalized anxiety disorder. One research group has proposed that valerian's modulation of GABA A receptors in animal models may explain valerian's antianxiety and sedative effects (Yuan et al., 2004). In 2012, 23.6% of the U.S. population surveyed complained of insomnia (Kessler et al., 2012). ...
... This ligand accepts one hydrogen by its carboxyl group from ASN 828 and forms other electrostatic and Van der Waals interactions with other eight amino acids. These interactions are weak, when compared to the response of valerenic acid to GABAA receptors (Yuan et al., 2004;Khom et al., 2007Khom et al., , 2010Trauner et al., 2008). In such situation, valerenic acid seems to have a secondary effect in SUR1 (Figure 6). ...
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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 nanoseconds Molecular Dynamics using a 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 substancia nigra 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.
... The following compounds, used as tobacco additives, may have an effect on the central nervous system: acetophenone, isoamyl alcohol, valerian oil, theobromine, and valerenic acid (Lington and Bevan 1994, Moreno 1978,, Oliva et al. 2004, Ortiz et al. 1999, Reynolds 1983a, Reynolds 1983b, Simons et al. 1985, Yuan et al. 2004). However, the fact that these additives may have an effect on the central nervous system (CNS) does not imply that they are addictive. ...
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The Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) has been asked to evaluate the role of tobacco additives in the addictiveness and attractiveness of tobacco products.The criteria for dependence established in humans indicate that tobacco has a high addictive potential, but it remains difficult to assess the addictiveness of individual additives. In animal studies the addictive potency of the final tobacco product cannot be assessed. The reinforcing potency of drugs is measured after intravenous injections and suggests that the abuse liability of pure nicotine is weaker than the addictive potential of tobacco products in humans. The currently used methods to define addictiveness of nicotine and additives are thus not considered adequate. In humans, the positive correlation between tobacco consumption and dependence suggests that individuals with high nicotine levels in their blood are more dependent. In animal studies using self-administration, an inverted U-shaped dose-response curve has generally been revealed suggesting that the addictiveness of nicotine is not directly linear with the dose. There is however substantial variation in the response to nicotine in both animals and humans, and genetic factors probably play an important role. No tobacco additives which are addictive by themselves have so far been identified. However, sugars, polysaccharides and cellulose fibres which are naturally present in tobacco, or sugars added in high quantities to most tobacco products, give rise to numerous aldehydes, such as acetaldehyde, in tobacco smoke. Acetaldehyde given intravenously is self-administered and enhances the addictiveness of nicotine in experimental animals. Additives that facilitate deeper inhalation (e.g. menthol) or inhibit the metabolism of nicotine may enhance the addictiveness of nicotine indirectly. Substances such as ammonia that increase the pH of the tobacco and the smoke, result in higher amounts of uncharged nicotine. However, it is uncertain if more nicotine is absorbed with higher smoke pH. For smokeless tobacco it seems that an increased pH enhances nicotine absorption in the mouth. The methods used to quantify the addictive potency of additives have limitations because of technical challenges in experimentally manipulating the presence or absence of an additive in a tobacco product. Such experiments require large technical and financial resources. In addition, there are ethical issues if testing in humans is considered. Due to these limitations, the available methodologies are not considered adequate. A number of technical characteristics of cigarettes (paper, filter, packing, geometry) influence the content of different substances in the smoke and the size of smoke particles. Many smokers compensate for a lower dose of nicotine by increasing puff volume and frequency, and by deeper inhalation. The particle size of the smoke aerosol does not seem to substantially influence the exposure to nicotine. The technical characteristics of cigarettes may thus modulate smoking behaviour but it is uncertain if this leads to a higher risk of addiction. Attractiveness is defined as the stimulation to use a product. The attractiveness of tobacco products may be increased by a number of additives but is also influenced by external factors such as marketing, price etc. Animal models do not currently exist for the assessment of attractiveness. In humans, the attractiveness of individual tobacco products may be compared in panel studies, surveys, and by experimental measures. Another method is to experimentally adjust tobacco products to exclude or include individual additives and test responses to them. However, this type of research is difficult due to ethical considerations that will usually preclude human testing of tobacco products, particularly among non-users or children. The use of fruit and candy flavours seems to favour smoking initiation in young people. Menthol also attracts a number of smokers, in particular African Americans. Some additives decrease the harshness and increase the smoothness of the smoke. Certain additives yield a full and white smoke and other additives reduce the lingering odour of the smoke in order to favour the acceptability of smoking to people around. Additives considered attractive may in principle lead to brand preference or a higher consumption of tobacco products. However, it remains difficult to distinguish the direct effects of these additives from indirect effects such as the marketing towards specific groups.
... Other studies revealed binding of valerian extract to GABA receptors, but the functional effect of the binding was not demonstrated. Data from the study of Yuan et al [37] and Trauner et al [38] suggest that the pharmacological effects of valerian extract and valerenic acid are mediated through modulation of GABAA receptor function. By passive diffusion valerenic acid is known to penetrate into the central nervous system trans cellular. ...
Article
Full-text available
Valerian (Valeriana officinalis) belonging to valerianaceae family is a well known herb and medicinal plant that has been widely used all over the world especially in Europe, China and Middle East. It is widely used as a sleep aid and sedative in many parts of the world but is also known to relax smooth muscle, hence used for treating stomach and intestine cramps. Alkaloids, terpenes, organic acids and its derivatives, valepotriates and flavones are the known pharmacologically active compounds found in valerian extract. In general, it is accepted that the valepotriates are the compounds responsible for the sedative activity of the Valerianaceae. The present article aims at reviewing the recent reports on its constituents, traditional use, clinical use and scientific verification of pharmacological actions of valerian.
... Valeriana officinalis (Valerianaceae) most widely used in Europe and USA contains sesquiterpene valerenic acid ( Figure 6). Yuan et al., [93] demonstrated that a commercially available valerian extract and valerenic acid inhibit GABA A receptor agonist muscimol-sensitive neurons in neonatal rat brainstem preparations with IC 50 values of 240 µg/mL and 23 µM, respectively. These effects were antagonized by GABA A receptor antagonist bicuculline at 10 µM. ...
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The majority of currently used anesthetic agents are derived from or associated with natural products, especially plants, as evidenced by cocaine that was isolated from coca (Erythroxylum coca, Erythroxylaceae) and became a prototype of modern local anesthetics and by thymol and eugenol contained in thyme (Thymus vulgaris, Lamiaceae) and clove (Syzygium aromaticum, Myrtaceae), respectively, both of which are structurally and mechanistically similar to intravenous phenolic anesthetics. This paper reviews different classes of phytochemicals with the anesthetic activity and their characteristic molecular structures that could be lead compounds for anesthetics and anesthesia-related drugs. Phytochemicals in research papers published between 1996 and 2016 were retrieved from the point of view of well-known modes of anesthetic action, that is, the mechanistic interactions with Na⁺ channels, γ-aminobutyric acid type A receptors, N-methyl-D-aspartate receptors and lipid membranes. The searched phytochemicals include terpenoids, alkaloids and flavonoids because they have been frequently reported to possess local anesthetic, general anesthetic, antinociceptive, analgesic or sedative property. Clinical applicability of phytochemicals to local and general anesthesia is discussed by referring to animal in vivo experiments and human pre-clinical trials. This review will give structural suggestions for novel anesthetic agents of plant origin.
... 11 Valepotriates and valerenic acid lead to an increase of Gamma-aminobutyric acid (GABA) in the central nervous system and are responsible for the anxiolytic effect of Valeriana offi cinalis. 12 In our experiment, individual extract of this plant reduces signifi cantly the Immobility time in the Forced swim test. Similar results are obtained in a study of Hattesohl et al. 13 However, in our results the reduction of the immobility time for the combination is higher compared to the re- duction caused by both Hypericum perforatum and Valeriana offi cinalis alone as individual extracts. ...
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Background: Chronic stress is one of the main factors which lead to depression - a psychiatric disorder affecting millions of people and predicted to be the second ranked cause of premature death in 2020. Depression is often associated with cognitive disturbances and memory deficit. Plant based therapy could be effective in the treatment of mild to moderate depression due to its low level of adverse reaction, its good tolerability and compliance. Materials and methods: 72 male Wistar rats, divided in 9 groups were given orally for 8 weeks two combinations of dry plant extracts - Antistress I and Antistress II and five individual dry extracts obtained from Serratula coronata, Hypericum perforatum, Valeriana officinalis, Crataegus monogyna and Melissa officinalis. The animals were exposed to a chronic unpredictable mild stress for 8 weeks. The depression-like symptoms were evaluated with Forced swim test while the assessment of the memory deficit was performed with Novel object recognition test. Results: Antistress II demonstrates antidepressant effect while Antistress I doesn't improve the depressive-like symptoms. The individual extracts of Hypericum perforatum and Valeriana officinalis also possess antidepressant properties. Antistress II improves the cognition as well as the individual extracts of Hypericum perforatum, Valeriana officinalis and especially Serratula coronata. Dry extract from Serratula tend to have the best effect regarding the recognition memory. The effect of Antistress I on memory deficit is negligible. Conclusions: Antistress II possesses antidepressant effect and improves the recognition memory while Antistress I doesn't demonstrate any of the above-described effects.
... Valerenic acid (182), isolated from Valeriana officinalis, caused a potentiation of GABA-induced chloride currents of 400% (at a concentration of 100 µM) with an EC 50 value of 13.6 µM [135], thus confirming earlier reports of the possible GABAergic mechanism of valerian extracts [136]. In an EPM test, valerenic acid prolonged the time spent in the open arms at a dose of 3 mg/kg [137]. ...
Article
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GABA(A) receptors are ligand-gated ion channels consisting of five subunits from eight subfamilies, each assembled in four hydrophobic transmembrane domains. This pentameric structure not only allows different receptor binding sites, but also various types of ligands, such as orthosteric agonists and antagonists, positive and negative allosteric modulators, as well as second-order modulators and non-competitive channel blockers. A fact, that is also displayed by the variety of chemical structures found for both, synthetic as well as nature-derived GABA(A)-receptor modulators. This review covers the literature for natural GABA(A)-receptor modulators until the end of 2017 and discusses their structure-activity relationship.
... The rhizome extract contains sesquiterpenes which primarily includes valerenic acid (VA), isovalerenic acid (IVA), acetoxy valerenic acid (AVA) and hydroxy valerenic acid (HVA), and is primarily known for their tranquilizer activities (Bos et al. 1996;Jugran et al. 2019). The pharmacological effects of its extract are generally attributed to VA and its derivatives that act on GABA receptors of the central nervous system (Becker et al. 2014;Yuan et al. 2004). In addition, its rhizomes also contain essential oil (0.05-1.66%) having an array of applications in aromatic and pharmaceutical industries (Singh et al. 2010). ...
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In vitro adventitious roots were induced from leaves of Valeriana jatamansi to assess their potential as a sustainable alternative to extract pharmaceutically important phytoconstituents. Among the different media used, a significantly (p ≤ 0.05) high root induction (90%) was achieved on Schenk and Hildebrandt (SH) medium fortified with 9.84 µM indole-3-butyric acid (IBA). In addition, various process parameters i.e. IBA concentration, sucrose and medium strength were also optimized under submerged cultivation. The maximum fresh root biomass (144.09 ± 11.36 g/L) with a high relative growth rate (2.01 ± 0.04) and growth index (13.41) was achieved in half-strength SH medium having 2% sucrose and 4.92 µM IBA. Further, a significantly high yield of total valerenic acid derivatives [1525.14 µg/g dry weight (DW)] was recorded in adventitious roots as compared to donor plant parts. Individually, valerenic acid (506.27 µg/g DW) was accumulated higher in plant rhizomes, while acetoxyvalerenic (534.91 µg/g DW) and hydroxyl valerenic acid (919.57 µg/g DW) in adventitious roots. Interestingly, hydroxy valerenic acid was unmeasurable in donor plant parts. The phenolic compounds were also found maximum in adventitious roots (451.85 µg/g DW) with the dominance of pharmaceutically important kaempferol and rutin. A substantial increase in phytochemicals was evident at subsequent culture stages with shortened in vitro cultivation cycle (2 months) than field-grown plants (24 months). Moreover, adventitious roots also accumulated 0.059% essential oil with patchouli alcohol (24%) as a key constituent. Conclusively, an enriched metabolic profile and substantially shorter growth cycle under submerged cultivation undoubtedly demonstrated the potential of induced V. jatamansi adventitious roots as a feasible source of phytoconstituents.
... For example, the pharmacological effects of valerian extract and valerenic acid are thought to be mediated through modulation of gamma-aminobutyric acid receptor function. 42 Assays evaluating neuronal cell firing using multielectrode arrays may be useful in evaluating lots of valerian root extract. Furthermore, institution of a testing framework that utilizes chemometric profiling coupled with QSAR modeling, similar to Little et al., could provide a mechanism to prioritize and predict assay panels that will provide relevant toxicological and biological activity information based on the chemical profile of the botanical test substance. ...
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Introduction: Recent nationwide surveys found that natural products, including botanical dietary supplements, are used by ∼18% of adults. In many cases, there is a paucity of toxicological data available for these substances to allow for confident evaluations of product safety. The National Toxicology Program (NTP) has received numerous nominations from the public and federal agencies to study the toxicological effects of botanical dietary supplements. The NTP sought to evaluate the utility of in vitro quantitative high-throughput screening (qHTS) assays for toxicological assessment of botanical and dietary supplements. Materials and Methods: In brief, concentration–response assessments of 90 test substances, including 13 distinct botanical species, and individual purported active constituents were evaluated using a subset of the Tox21 qHTS testing panel. The screen included 20 different endpoints that covered a broad range of biologically relevant signaling pathways to detect test article effects upon endocrine activity, nuclear receptor signaling, stress response signaling, genotoxicity, and cell death signaling. Results and Discussion: Botanical dietary supplement extracts induced measurable and diverse activity. Elevated biological activity profiles were observed following treatments with individual chemical constituents relative to their associated botanical extract. The overall distribution of activity was comparable to activities exhibited by compounds present in the Tox21 10K chemical library. Conclusion: Botanical supplements did not exhibit minimal or idiosyncratic activities that would preclude the use of qHTS platforms as a feasible method to screen this class of compounds. However, there are still many considerations and further development required when attempting to use in vitro qHTS methods to characterize the safety profile of botanical/dietary supplements.
... Marder et al. (2003) also produced synergistic effects on sleep-inducing effects when 2 S (-) Hesperidin was combined with 6-methylapigenin [164]. Valerenic acid is a sesquiterpenoid that is believed to modulate the GABA A receptor through potentiation of other components [165]. Linarin is a flavonoid glycoside that also has sedative and sleepenhancing properties, the mechanism of which is still unclear. ...
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Functional beverages can be a valuable component of the human diet with the ability to not only provide essential hydration but to deliver important bioactive compounds that can contribute to chronic disease treatment and prevention. One area of the functional beverage market that has seen an increase in demand in recent years are beverages that promote relaxation and sleep. Sleep is an essential biological process, with optimal sleep being defined as one of adequate duration, quality and timing. It is regulated by a number of neurotransmitters which are, in turn, regulated by dietary intake of essential bioactive compounds. This narrative review aimed to evaluate the latest evidence of the sleep promoting properties of a selection of bioactive compounds (such as L-theanine and L-tryptophan) for the development of a functional beverage to improve sleep quality; and the effectiveness of traditional sleep promoting beverages (such as milk and chamomile). Overall, the bioactive compounds identified in this review, play essential roles in the synthesis and regulation of important neurotransmitters involved in the sleep-wake cycle. There is also significant potential for their inclusion in a number of functional beverages as the main ingredient on their own or in combination. Future studies should consider dosage; interactions with the beverage matrix, medications and other nutraceuticals; bioavailability during storage and following ingestion; as well as the sensory profile of the developed beverages, among others, when determining their effectiveness in a functional beverage to improve sleep quality.
... Several plant compounds have therefore been studied to determine scientifically their mechanism of action. The valerenic acid is responsible for the effects of V. officinalis on GABAARs [36]. However, its site of action remains unknown. ...
... The body system affected was the nervous system, which is consistent with its use for hypnotic effect to calm neuropsychological disorders such as anxiety (n = 16, 48.5%, Fig. 5). ADRs describing extreme fatigue may be caused by an increase in the amount of GABA through modulation of GABA A receptor function [15]. ...
Article
Objective: Assessing adverse drug reactions (ADRs) is a proven method to estimate the safety of medicines. The ADRs to herbal medicines in Australia (and by inference, the safety of herbal medicines in Australia) remain unknown. This study examines spontaneous ADR cases to four of the most popular herbs in Australia from 2000 to 2015: echinacea (Echinacea purpurea), valerian (Valeriana officinalis), black cohosh (Actaea racemosa) and ginkgo (Ginkgo biloba). Methods: ADRs of echinacea, valerian, black cohosh and ginkgo reported to the Australian Therapeutic Goods Administration (TGA) between 2000 and 2015 were obtained from the TGA database. Data were collated and analysed according to age, sex, severity, type of ADR and body system affected. Statistics were calculated using GraphPad Prism software. Results: Most ADRs were mild or moderate. However, every herbal medicine was associated with life-threatening ADRs. In each life-threatening case, the herbal medicine was taken concomitantly with prescription medications. Black cohosh was associated with a significant number of severe ADRs (30.3% of the total), with 39.4% of these ADRs being associated with abnormal hepatic function, hepatitis or hepatotoxicity. Conclusion: This study highlights the lack of public awareness with regard to herb-drug interactions, since most of the severe ADRs involved a herb-drug interaction.
... Valerian morphological parts contain terpenoids, alkaloids, phenolics, flavonoids, and lignans ( Fig. 17.6) of various forms [57,59]. Generally, the most described valerian compounds with established biological activity include valepotriates, valtrate, didrovaltrate, valerenic acid, valeretrenal, actinidine, free amino acids such as glutamate, tyrosine, glutamine, and GABA itself [60][61][62]. In one study, phytochemical screening of root extracts reveals the presence of a variety of phenolics such as olivil, pinoresinol, trans-p-hydroxyphenyl-propenoic acid, 8-hydroxypinoresinol, pinorespiol, 8-hydroxy-7-epipinoresinol, isovanillin, and ferulic acid among others [58]. ...
Chapter
Insomnia and sleep apnea represent the most prevalent sleep disorders worldwide. Incidences are discouraging, with perhaps less attention in some parts, and the complexity in the pathophysiologies of the two diseases pose a major challenge to clinicians and researchers. Mainstream therapeutic regimens are afflicted by adverse side effects, laborious, demanding enormous amounts of money, and are in particular, less accessible to the vast majority. Traditional medicine remains critically the “Hobsons’s choice” and stands out as a scaffold for the development of novel drugs with more desirable pharmacological attributes. This chapter covers the pathophysiological attributes of insomnia and sleep apnea, pointing out their interplay, possible biomarkers, and targets for both conventional and alternative therapeutic approaches. The chapter further delves more into the role of selected most important plant species in the management of insomnia and sleep apnea. Realizing the importance of phytochemistry in the drug discovery endeavor, the chapter, as well, underscores the phytochemical profile underlying the neuropharmacological relevance of each plant to its possible effectiveness in improving sleep quality.
... Notably, small differences have been reported between extracts from plants grown in different conditions or processed in a different manner, and large-scale producers have standardized protocols of plant growth and extract preparation aimed at reducing variability [48]. Studies in tissue culture and animal models suggest that components of valerian extract (Valeriana officinalis L.) possess prominent dose-dependent GABA A agonistic activity [49,51]. 6-methylapigenin is a potent positive modulator of GABA A , possibly binding to the benzodiazepine site at the interface of α and γ subunits, whereas valerenic acid and valerenol have been shown to interact with the β subunit of the receptor [47,48]. ...
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Sleep is an essential component of physical and emotional well-being, and lack, or disruption, of sleep due to insomnia is a highly prevalent problem. The interest in complementary and alternative medicines for treating or preventing insomnia has increased recently. Centuries-old herbal treatments, popular for their safety and effectiveness, include valerian, passionflower, lemon balm, lavender, and Californian poppy. These herbal medicines have been shown to reduce sleep latency and increase subjective and objective measures of sleep quality. Research into their molecular components revealed that their sedative and sleep-promoting properties rely on interactions with various neurotransmitter systems in the brain. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that plays a major role in controlling different vigilance states. GABA receptors are the targets of many pharmacological treatments for insomnia, such as benzodiazepines. Here, we perform a systematic analysis of studies assessing the mechanisms of action of various herbal medicines on different subtypes of GABA receptors in the context of sleep control. Currently available evidence suggests that herbal extracts may exert some of their hypnotic and anxiolytic activity through interacting with GABA receptors and modulating GABAergic signaling in the brain, but their mechanism of action in the treatment of insomnia is not completely understood.
... Diazepam is a GABA agonist that binds specifically to Benzodiazepine receptor of GABA which result in inhibition of central nervous system activity. [17][18][19][20][21][22][23] GABRB3 is a heteromeric gene that encodes the GABA A receptor β 3 subunit, GABRB3 is a member of the GABA A receptor family gene which has a heterometric structure of pentameric ion channel ligand channels where it works from GABA. GABA A receptors are the major inhibitory transmitter receptors in the brain and the site of action of a variety of pharmacologically and clinically important drugs. ...
... 48) The sleep-promoting effects of several natural herbs also have been involved in the response to GABA receptors. 49,50) Licorice (Glycyrrhiza glabra, GG) has been shown to allosterically modulate GABA A -benzodiazepine receptors in a dose-dependent manner. 48) A recent study showed that Valerian/cascade mixture upregulates the GABA receptor in mRNA level. ...
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The aim of this study is to investigate the effects of romaine lettuce leaves extract (RE), skullcap root extract (SE) and their mixture on sleep behaviors in vertebrate models. HPLC analysis showed that RE contains lactucopicrin (0.02±0.01 mg/g extract), chlorogenic acid (4.05±0.03 mg/g extract), caffeic acid (2.38±0.03 mg/g extract), and chicoric acid (7.02±0.32 mg/g extract) as main phenolic compounds, while SE includes baicalin (99.4±0.5 mg/g extract), baicalein (8.28±0.21 mg/g extract), and wogonin (3.09±0.32 mg/g extract). The mixture of RE (100 mg/g extract) and SE (40 mg/g extract) increased total sleep time by 50.9% compared with the control in pentobarbital-induced sleep model. In electroencephalography (EEG) analysis, RE/SE mixture significantly increased Non-Rapid Eye Movement (NREM), in which delta wave was enhanced by around 40% compared with normal control, leading to the increase of sleep time. In caffeine-induced wake model, RE/SE mixture greatly decreased (53%) caffeine-induced wake time, showing a similar level to normal control. In addition, caffeine-induced decreased of NREM and delta wave effectively increased with RE/SE mixture; NREM and delta wave increased by 85% and 108%, respectively. Furthermore, RE/SE mixture was shown to bind to a gamma-aminobutyric acid type A (GABAA)-benzodiazepine (BZD) receptor stronger than RE or SE single extract. Taken together, RE/SE mixture effectively improved sleep behavior with the increase of NREM via GABAA-BZD receptor binding. RE/SE mixture can be used as an herbal agent for sleep disorders. Graphical Abstract Fullsize Image
... The valerian root extract and valerenic acid were described to display in vitro GABAergic effects on the brainstem of neonatal rats [79]. The findings indicated that the valerian extract at concentration of 3 mg/mL induced 29.6 ± 5.1% of inhibition with an IC 50 value of 240 ± 18.7 μg/mL, whereas valerenic acid at 100 μM induced a 22.2 ± 3.4% of inhibition (IC 50 = 23 ± 2.6 μM). ...
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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 treatment of gastrointestinal spasms. V. officinalis has a 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 gammaaminobutyric acid (GABA) receptors has been revealed to be the leading mechanism of the plant based on the existence of valerenic acid, several studies described interaction of valerenic acid with glutamergic receptors. In addition to valerenic acid; isovaleric acid, didrovaltrate, borneol, and some lignans have been also proposed to contribute to 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.
Article
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, and those of KG8 were significantly more than 10-times higher. Meanwhile, α-KA and kessyl glycol (KG) were 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.
Article
Background: In traditional medicine, the roots and rhizomes of Valeriana officinalis (Valerian) have been used to decrease gastrointestinal tract motility in intestinal spasms, colic and gastrointestinal disorders of nervous origin. It has been also suggested for alleviation of nausea. Objective: The aim of this study was to investigate the antiemetic effect of V. officinalis extract (aqueous-ethanolic) for documentation of reports available in traditional medicine. Methods: The antiemetic effect of V. officinalis extract (aqueous-ethanolic) against emesis induced by copper sulfate (60 mg/kg, orally) and ipecac (600 mg/kg, orally) was investigated. The number of emesis was counted for 50 and 20 minutes after copper sulfate and ipecac administration, respectively. Results: The extract at doses of 0.28, 0.49 and 0.7 g/kg (ip) exhibited significant protection against copper sulfate and ipecac induced - emesis. The dose of 0.7 g/kg lowered the number of copper sulfate induced- and ipecac induced - emesis of negative control (saline), respectively 65.704% and 79.88%. Conclusion: According to the results, the antiemetic effect of Valerian was significant and it confirms the traditional uses of Valerian in attenuation of nausea.
Chapter
Multiple plants were used traditionally, throughout history, for a variety of purposes. Many of these traditionally used plants produce various molecules, which directly, and sometimes with high affinity, bind and activate or block from activation human receptors. Among the most effective molecules are those that serve as ligands to receptors found in the central nervous system (CNS) of the human brain. Here we present some of these plants, their traditional uses, the molecules they produce, and some of their modes of action. In accordance, the first part of the chapter describes the traditional, medicinal, and recreational uses of the plants. The second part of the chapter reviews the compounds present in these different plants and their binding properties to CNS receptors. Lastly, insight and suggestions will be provided into the man-made evolution of these plants, which might have led to their high potency.
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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.
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Ayurveda, the oldest system of medicines, describes the disease conditions under eight branches. The diseases related to supraclavicular region have been described under the category of urdhajatrugata rogas of Shalakya (E.N.T) tantra. Many of the diseases related to head, eye, ear, and nose have been dealt under these headings. However, the nighantu granthas (Ayurvedic lexicons), the compendia describing the pharmacological properties of plants, have not described the drugs based on the organ system specific actions. Very few texts are available till date which gives vivid description regarding the exclusive management of Shalakya (E.N.T) related disorders. It is observed that nighantus (Ayurvedic lexicons) of medieval periods have described many herbal drugs in the context of urdhajatrugata chikitsa, but in a scattered way.
Chapter
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.
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With increases in the prevalence of psychiatric and behavioral disorders and rapid advances in the development of new drug therapies, there is an increasing need to present the science behind these developments. Students and educators are often confronted with conflicting and exaggerated claims about the effectiveness of drugs. As recently as ten years ago, the mechanisms of action of many medications prescribed for common psychological disorders were not well understood, even by the scientists developing them. Now, drug treatment has advanced to a stage where drugs are designed for their effects on specific receptors, membrane proteins, or secondary messengers within particular cells in the brain. This text introduces a sufficient background in neuroanatomy and physiology so students can comprehend the necessary details of drug action. Psychopharmacology, Second Edition, presents its subject matter in the context of the behavioral disorders they are designed to treat, rather than by traditional drug classifications. Students are often familiar with the major diagnostic categories, so presenting psychopharmacology as it pertains to these familiar disorders strengthens their understanding of the physiology and neurochemistry underlying them as well as the approaches to their treatment. Each disorder is discussed from a historical context along with diagnostic criteria and descriptions of typical cases. In addition, what we presently know about the underlying pathology of each disorder is carefully described. A critical examination of drug claims is missing from most psychopharmacology texts, but is offered here. Students will read about the most current research available from a critical perspective. When alternatives to traditional drug therapies are supported by research, these studies are presented as well. Throughout, this text discusses how drug effectiveness is measured in both human and animal studies. Psychopharmacology has contributed significantly over the past 75 years to the treatment of severe psychological disorders as well as to our understanding of the brain and human behavior. This symbiotic relationship between psychopharmacology and the neural and behavioral sciences will continue long into the future. This fully updated second edition is ideal for undergraduate and pre-professional students, and includes a robust companion website.
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Valerian (Valeriana officinalis) belonging to valerianaceae family is a well-known herb and medicinal plant that has been widely used all over the world especially in Europe, China and Middle East. It is widely used as a sleep aid and sedative in many parts of the world but is also known to relax smooth muscle, hence used for treating stomach and intestine cramps. Alkaloids, terpenes, organic acids and its derivatives, valepotriates and flavones are the known pharmacologically active compounds found in valerian extract. In general, it is accepted that the valepotriates are the compounds responsible for the sedative activity of the Valerianaceae. The present article aims at reviewing the recent reports on its constituents, traditional use, clinical use and scientific verification of pharmacological actions of valerian.
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The aim of this study was to examine whether and how different odorants placed on the bodies of female mice, but having no reward value for the males, affect courtship and mating behaviour of male mice towards females in oestrus and thus emitting female pheromones. In this manner, certain consequences of concurrent activation of the main olfactory system and the vomeronasal system were investigated. Four different odorants (white musk, lavender, peppermint and valerian) were used for swabbing female mice in oestrus. Using a total of 160 sexually naive outbred mice of both sexes, divided for each of 4 odorants into controls (not swabbed with odorant) and two experimental groups, in the experimental group I the females observed previously as controls were swabbed with one of the 4 odorants, while in the experimental group II, new naive females were swabbed with one of the 4 odorants. The females were observed in individual cages for 30 min. each, together with a respective sexually naive male. The latency between introduction of a male into a cage with a previously swabbed female and initiation of courtship and mating behaviours by males (sniffing, circling, misdirected mounting, copulation failures, successful copulation) was recorded. Latency to the occurrence of all sexual behaviours was significantly longer in experimental groups compared to controls. Latency to initiation of courtship behaviour, especially sniffing and circling, was shorter towards females swabbed with peppermint odour than for other odorants, indicating no aversion to this odour. However, the peppermint odour completely inhibited copulation. It is concluded that alien volatile odours with no reward value nevertheless exert differentiated suppressing effects on female mice pheromones inducing courtship and mating behaviour. Thus, it is hypothesized that the activation of the main olfactory system suppresses the accessory vomeronasal system.
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Introduction: Controversy and uncertainty exist about the use of benzodiazepine receptor agonists (BZRAs) in pain management. This article curates available research to determine the appropriate role of BZRAs in the course of pain management, and how prescribers might address these challenges. Methods: A narrative review was performed to determine the appropriate role of BZRAs in pain management and to develop practice recommendations. Publications were identified by a search of PubMed, references of retrieved reports, guidelines, and the author's personal files. Results: BZRAs were found to have analgesic benefit for two pain conditions: burning mouth syndrome and stiff person syndrome. Absence of research, heterogeneity of trials, and small sample sizes precluded drawing conclusions about efficacy of BZRAs for the other 109 pain conditions explored. Data supports the use of BZRAs to treat co-occurring insomnia and anxiety disorders but only when alternatives are inadequate and only for short periods of time (2-4 weeks). The utility of BZRAs is limited by loss of efficacy that may be seen with continued use and adverse reactions including physiologic dependence which develops in 20-100% of those who take these agents for more than a month. Conclusions: BZRAs are often used inappropriately in pain management. Their initiation and duration of use should be limited to a narrow range of conditions. When prescribed for 4 weeks or more, patients should be encouraged to discontinue them through a supported, slow tapering process that may take 12-18 months or longer.
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Eschscholtzia californica Cham. and Valeriana officinalis L. have long been used for the management of sleep disorders and anxiety. Use of a fixed combination of these two plant extracts (Phytostandard® d’Eschscholtzia et de Valériane, PiLeJe Laboratoire, France) was investigated in an observational study. Adults with adjustment insomnia according to the criteria of the International Classification of Sleep Disorders and with an insomnia severity index (ISI) score >7 enrolled by GPs took a maximum of four tablets of the eschscholtzia and valerian combination every night for four weeks. Within one month, ISI score decreased by approximately 30% (from 16.09 ± 3.67 at inclusion (V1) to 11.32 ± 4.78 at 4 weeks (V2); p < 0.0001). Night sleep duration significantly increased between the first and the fourth week of supplement intake, sleep efficiency increasing from 78.4% ± 12.5 to 84.6% ± 10.2 (p = 0.002). There was no improvement in sleep latency. The number of awakenings decreased by approximately 25% and their total duration by approximately 25 min. Anxiety score significantly decreased by 50% from 13.9 ± 7.3 at V1 to 6.7 ± 6.3 at V2 (p < 0.0001). The supplement was well tolerated. These results suggest that the tested combination of eschscholtzia and valerian extracts could be beneficial for the management of insomnia in adults and deserves further investigation.
Chapter
There have been many advancements in the treatment of generalized anxiety and post traumatic stress disorder. Attention to these disorders has increased with recent world events; however, continued efforts are needed to improve their diagnosis, treatment, and prevention. Objective of this review examines herbs commonly used for generalized anxiety and some other psychiatric symptoms and advantages associated with their use.
Thesis
De tout temps et dans de nombreuses cultures, l’Homme a cherché dans son environnement, et plus particulièrement dans les plantes, les moyens de se soigner. Aujourd’hui, même si notre médecine moderne a permis l’émergence d’un arsenal thérapeutique efficace, la phytothérapie connait un regain d’intérêt. Cette thèse a pour but de constituer une aide utile à l’usage du praticien souhaitant conseiller la phytothérapie comme traitement de l’insomnie. Nous avons ainsi fait un rappel de l’architecture et de la physiologie du sommeil ainsi que des différents types d’insomnies. Rappel suivi d’un retour en arrière sur les usages de drogues végétales dans les médecines traditionnelles. Nous avons abordé le rôle du pharmacien et son conseil, et présenté l’état de nos connaissances sur les principales drogues végétales disponibles et indiquées dans le traitement de l’insomnie. En plus de présenter ces différentes drogues végétales, nous nous sommes efforcés de confirmer les propriétés qui leurs sont traditionnellement attribuées. Nous avons ainsi compilé un grand nombre d’études scientifiques qui ont permis de citer de nombreux principes actifs, mécanismes d’action, et de confirmer l’efficacité de tel ou tel extrait de drogue végétale. Nous avons aussi regroupé les effets indésirables, cas de toxicité, intéractions et contreindications citées dans la littérature. De plus cette étude s’est étendue aux drogues permettant de traiter des facteurs importants souvent associés à l’insomnie : anxiété, dépression ou encore fatigue diurne.
Article
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.
Article
Sleep problems have become common among people today. Sleep disorders are closely associated with physiological and psychological diseases. Among the ways of improving objective or subjective sleep quality, controlling elements associated with food intake can be more efficient than other methods in terms of time and cost. Therefore, the purpose of this study was to understand the effects of nutrients and natural products on sleep. An extensive literature search was conducted, and related articles were identified through online databases, such as Elsevier, Google Scholar, PubMed, Springer, and Web of Science. Expert opinion, conference abstracts, unpublished studies, and studies published in languages other than English were excluded from this review. The effects of macronutrients and diet adjustment on sleep differed. Although not all nutrients independently affect sleep, they comprehensively affect it through tryptophan metabolism. Furthermore, natural foods related to GABA have an effect on sleep similar to that of sleeping pills. Taken together, our results suggest that humans can control both their objective and subjective sleep quality based on their lifestyle and food consumption. However, until now, direct studies on the relationship between human sleep and nutrition, such as clinical trials, have been insufficient. As both objective and subjective sleep quality are the factors determining the quality of life of individuals, further studies on those are needed to improve it.
Book
The authoritative and comprehensive modern textbook on western herbal medicine - now in its second edition This long-awaited second edition of Principles and Practice of Phytotherapy covers all major aspects of herbal medicine from fundamental concepts, traditional use and scientific research through to safety, effective dosage and clinical applications. Written by herbal practitioners with active experience in clinical practice, education, manufacturing and research, the textbook is both practical and evidence based. The focus, always, is on the importance of tailoring the treatment to the individual case. New insights are given into the herbal management of approxiately 100 modern ailments, including some of the most challenging medical conditions, such as asthma, inflammatory bowel disease and other complex autoimmune and inflammatory conditions, and there is vibrant discussion around the contribution of phytotherapy in general to modern health issues, including health ageing. Fully referenced throughout, with more than 10, 000 citations, the book is a core resource for students and practitioners of phytotherapy and naturopathy and will be of value to all healthcare professionals - pharmacists, doctors, nurses - with an interest in herbal therapeutics.
Article
The interaction with GABA-BDZ-Cl receptor complex in rat brain has been investigated in vitro for hydroalcoholic and aqueous extract obtained from the roots of V. officinalis. The affinity of lipophilic and aqueous fraction obtained from the hydroalcoholic extract has also been studied together with that of hydroxyvalerenic acid and dihydrovaltrate. Both hydroalcoholic and the aqueous total extract, as well as the aqueous fraction derived from hydroalcoholic extract showed affinity for the GABA-A receptor. The chemical nature of the compound(s) responsible for such an activity is not correlable with sesquiterpenes or valepotriates. The lipophilic fraction of the hydroalcoholic extract as well as dihydrovaltrate showed affinity for the barbiturate receptor and, even if to a lesser extent, for the peripheral benzodiazepine receptors. The bulk of these evidences indicate that the interaction of unknown constituents, present in total extracts, with GABA-A receptors could represent the molecular base for the sedative effect observed both in man and experimental animals. For the hydroalcoholic extract, a contribute to the sedative effect cannot be excluded due to the interaction of their valepotriate constituents with the allosteric sites of GABA receptors controlling chloride anions influx.
Article
OBJECTIVE To review the epidemiology, etiology, and classification of insomnia and provide an overview of the pharmacologic therapy of insomnia. Novel nonbenzodiazepine hypnotics including zolpidem, zopiclone, and zaleplon, as well as nonprescription products such as valerian and melatonin, are reviewed in detail. DATA SOURCES A MEDLINE search was performed to identify relevant clinical studies, case reports, abstracts, and review articles published between April 1992 and December 1997. Key search terms included insomnia, benzodiazepines, zolpidem, zopiclone, zaleplon, Cl 284,846, melatonin, and valerian. Additional references were obtained from the lists of review articles and textbooks. DATA EXTRACTION AND SYNTHESIS Data concerning the safety and efficacy of the hypnotic agents were extracted from all available clinical trials and abstracts. Background information regarding insomnia, benzodiazepines, and other hypnotics was extracted from the most current literature, including review articles and textbooks. CONCLUSIONS New developments in benzodiazepine receptor pharmacology have introduced novel nonbenzodiazepine hypnotics that provide comparable efficacy to benzodiazepines. Although they may possess theoretical advantages over benzodiazepines based on their unique pharmacologic profiles, they offer few, if any, significant advantages in terms of adverse effects. Over-the-counter agents such as valerian and melatonin may be useful in alleviating mild, short-term insomnia, but further clinical trials are required to fully evaluate their safety and efficacy.
Article
The enzym system 2-oxoglutarataminotransferase/semisuccinaldehydoxireductase (E. C. 2.6.1.19/E.C. 1.2.1.16, Gabase) catalyzing the catabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) is inhibited by mmol/l concentrations of valerenolic acid (20%) and acetylvalerenolic acid (38%). 1 mmol/l L-glutamic acid inhibited 59%, 0.1 mmol/l chlorogenic acid 69%.
Article
An ethanol total extract of the roots of Valeriana officinalis L. in doses equivalent to 0.5–800 mg valerian root/kg b.w.i.p. was tested in male mice for possible neuropharmacological efficacy and in this respect compared with diazepam and haloperidol. The extract did not modify spontaneous motility, nociception or body temperature, and did not produce palpebral ptosis. However, it was anticonvulsant against picrotoxin (but not pentetrazol and harman) with an ED50 between 4.5 and 6 mg/kg and it prolonged thiopental anaesthesia. After fractionation of the crude extract, the antipicrotoxin activity was present mainly in the methylene chloride fraction (ED50=0.25 mg/kg). Pure valerenic acid (12.5 mg/kg b.w.i.p.) also exerted an antipicrotoxin effect.
Article
By using a multibarrelled microelectrode, the possibility that putative transmitters may influence on the field potential evoked in the solitary tract nucleus by electrical stimulation of the carotid sinus nerve (the NTS response) was examined electrophysiologically in the cat. After iontophoretic application of a selective antagonist to the putative transmitter, it was determined whether or not the NTS response was influenced. Both substance P antagonist and naloxone altered the NTS response recorded in the depressor and apneic (or hypopneic) response zone as well as in the pressor and apneustic (or inspiratory) response zone throughout the rostral, intermediate and commissure regions, suggesting that substance P and opioid peptide may play the role of excitatory transmitters. Under the polarizing cathodal current which may activate inhibitory inputs to the site of the NTS response, bicuculline and prazosin strongly enhanced the NTS response recorded in the pressor and apneustic zone, while naloxone weakly enhanced the NTS response recorded in the depressor and apneic zone. These results suggest that γ-aminobutyric acid, α-adrenergic agonist and opioid peptide may have an inhibitory influence on the NTS response.
Article
Valerian root contains two substances of special pharmacological interest--valepotriates and sesquiterpenes. The former, which has been used for standardization of the drug, is cytotoxic. The latter has no such effect. Both have sedative effects. A double blind test has been carried out on a preparation (VALERINA NATT) containing primarily sesquiterpenes. When compared with placebo it showed a good and significant effect on poor sleep (p less than 0.001). Forty-four percent reported perfect sleep and 89% reported improved sleep from the preparation. No side effects were observed.
Article
The effect of an aqueous extract of valerian root on sleep was studied in two groups of healthy, young subjects. One group (N = 10) slept at home, the other (N = 8) in the sleep laboratory. Sleep was evaluated on the basis of questionnaires, self-rating scales and night-time motor activity. In addition, polygraphic sleep recordings and spectral analysis of the sleep EEG was performed in the laboratory group. Under home conditions, both doses of valerian extract (450 and 900 mg) reduced perceived sleep latency and wake time after sleep onset. Night-time motor activity was enhanced in the middle third of the night and reduced in the last third. The data suggest a dose-dependent effect. In the sleep laboratory, where only the higher dose of valerian was tested, no significant differences from placebo were obtained. However, the direction of the changes in the subjective and objective measures of sleep latency and wake time after sleep onset, as well as in night-time motor activity, corresponded to that observed under home conditions. There was no evidence for a change in sleep stages and EEG spectra. The results indicate that the aqueous valerian extract exerts a mild hypnotic action.
Article
The effect of an aqueous extract of valerian (Valeriana officinalis L.) root on subjectively rated sleep measures was studied on 128 people. Each person received 9 samples to test (3 containing placebo, 3 containing 400 mg valerian extract and 3 containing a proprietary over-the-counter valerian preparation). The samples, identified only by a code number, and presented in random order, were taken on non-consecutive nights. Valerian produced a significant decrease in subjectively evaluated sleep latency scores and a significant improvement in sleep quality: the latter was most notable among people who considered themselves poor or irregular sleepers, smokers, and people who thought they normally had long sleep latencies. Night awakenings, dream recall and somnolence the next morning were relatively unaffected by valerian. With the proprietary valerian-containing preparation, the only change was a significant increase in reports of feeling more sleepy than normal the next morning. Thus the questionnaire, simple to use and non-invasive, provides a sensitive means for detecting the effects of mild sedatives on different aspects of sleep in man. It also allows identification within the test population of the subgroups most affected.
Article
An in vitro neonatal rat preparation, consisting of the isolated caudal brainstem and stomach joined by the intact vagi, was developed using Sprague-Dawley rats. The animals were 0 to 4 days of age. This preparation provided an opportunity to investigate the extracellular and intracellular responses of neurons in the nucleus tractus solitarius (NTS) of the brainstem to electrical stimulation of subdiaphragmatic vagal fibers. The dorsal and ventral vagal branches were electrically stimulated at the point of the common subdiaphragmatic vagal trunk. The isolated preparation was superfused in a recording chamber at 28 degrees C with a modified Krebs solution, equilibrated with 95% O2 and 5% CO2. Suction microelectrodes, for electrical stimulation, were positioned on the common vagal trunk just below the diaphragm to evaluate extracellular and intracellular evoked responses in NTS. A total of 204 subdiaphragmatic vagally-evoked (SDVe) brainstem unitary responses in the NTS were recorded. The mean latency of the extracellular SDVe brainstem responses was 89 +/- 12.9 ms (mean +/- SD). The peripheral gastric effects of CCK-8 on SDVe unitary responses in NTS neurons were evaluated. The peptide caused a significant increase in the excitability of these NTS neurons which was blocked by the CCKA receptor antagonist L-364,718. Neurons in the NTS and the dorsal motor nucleus of the vagus which showed excitatory responses to vagal stimulation were filled with Lucifer Yellow to evaluate their morphology.
Article
The effect of an aqueous extract obtained from the roots of Valeriana officinalis was investigated on the uptake and release of GABA in synaptosomes isolated from rat brain cortex. Aqueous extract of valerian inhibited the uptake and stimulated the release of [3H]GABA, either in the absence or in the presence of K+ depolarization. The release was Na(+)-dependent and independent of the presence of Ca2+ in the external medium. It is concluded that valerian extract releases [3H]GABA by reversal of the GABA carrier, which is Na(+)-dependent and Ca(2+)-independent. This increase in [3H]GABA release appears to be independent from Na(+)-K(+)-ATPase activity and the membrane potential.
Article
The evaluation of a commercially available valerian root extract (Valdispert) revealed pronounced sedative properties in the mouse with respect to a reduction in motility and an increase in the thiopental sleeping-time. A direct comparison with diazepam and chlorpromazine revealed a moderate sedative activity for the tested extract. The extract showed only weak anticonvulsive properties.
Article
The role of GABAA and GABAB receptors in neuronal mechanisms of the baroreceptor reflex in the nucleus tractus solitarii (NTS) of the anesthetized and immobilized rabbits were investigated using a microiontophoretic technique. Baroreceptive neurons (BRNs) activated or depressed by baroreceptor stimulation (phenylephrine, 10 micrograms/kg, i.v.) were identified in the NTS (activated BRN (A-BRN) and depressed BRN (D-BRN), respectively). The GABAA antagonist bicuculline (40-80 nA) increased spontaneous activities of these neurons, but the GABAB antagonist phaclofen (80-160 nA) did not. Evoked responses of A-BRNs were potentiated by bicuculline and phaclofen, while the responses of D-BRNs were not clearly affected by these drugs. These results suggest that most of A- and D-BRNs are tonically inhibited by endogenous GABA acting on GABAA receptors, but not on GABAB receptors, and that GABAergic mechanisms suppressively modulate the baroreceptor reflex acting on GABAA and GABAB receptors of A-BRNs, but not of D-BRNs.
Article
This work studied in vitro the interaction of aqueous and hydroalcoholic extracts of Valeriana officinalis L. and compounds that are present in the extracts (amino acids and valerenic acid) with the GABAA (gamma-aminobutyric acid) receptor, using the [3H] muscimol binding technique to crude synaptic membranes from rat brain cortices. Both extracts displaced [3H]muscimol bound and this effect is probably due only to their amino acid content, specially GABA. This fact explains the in vitro effect of valerian extracts on GABAA receptor but not their sedative effect.
Article
gamma-Aminobutyric acid (GABA) is an important neurotransmitter that mediates inhibition in the vertebrate CNS. Until recently, two receptor subtypes were known: bicuculline-sensitive GABAA and baclofen-sensitive GABAB receptors. Several lines of evidence now indicate the existence of a third class of GABA receptor, which is distinct pharmacologically from GABAA and GABAB receptors and is found predominantly in the vertebrate retina. These novel GABAC receptors are Cl- pores. They are insensitive to drugs that modulate GABAA and GABAB receptors and are activated selectively by cis-4-aminoacrotonic acid.
Article
The nucleus tractus solitarii (NTS), which receives visceral afferent information from the cardiovascular, respiratory, gastrointestinal and taste systems, contains multiple neurotrasmitters and neuropeptides throughout its rostral to caudal extent. The neurotransmitters and neuropeptides immunoreactivity is located predominately in varicose fibers and small puncta throughout the neuropil. In addition, immunoreactive NTS neurons for a variety of neurotransmitters and neuropeptides are present in subnuclear regions. The neuroactive substances localized immunohistochemically in the NTS include acetylcholine, the neuropeptides, substance P, methionine- and leucine-enkephalin, β-endorphin, cholecystokinin, neurotensin, galanin, calcitonin gene-related peptide, somatostatin, FMRMamide, neuropeptide Y, angiotensin II, vasoactive intestinal polypeptide, vasopressin, oxytocin, thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, atrial natriuretic peptide, the catecholamines, dopamine, norepinephrine, epinephrine, serotonin, histamine and the amino acids, GABA and glutamate. The pattern of innervation for each neurotransmitter and neuropeptide is not homogeneously distributed throughout the NTS. Each substance has a unique pattern within the NTS as each subnuclear region contains different immunohistochemical staining patterns and densities of fibers. At the ultrastructural level both neurotransmitters and neuropeptides are present in synaptic terminals that are in contact with different parts of the neuronal membranes. Typically, the labeled terminals contain both small, clear vesicles and large, dense core vesicles with the exception of synaptic terminals containing acetylcholine, GABA and glutamate which do not typically have the large, dense core vesicles. The most frequent post-synaptic target are dendrites and spinous processes. Less frequently, synaptic contacts are present on the cell soma. Chem. Senses 21: 367–376, 1996.
Article
The firing frequency of baroreceptive neurons in the nucleus tractus solitarii (NTS) during microiontophoretic application of muscimol, a gamma-aminobutyric acid (GABA)A agonist, or baclofen, a GABAB agonist, was monitored in anesthetized rats. Muscimol decreased the spontaneous discharge of 69 of 73 (94.5%) NTS baroreceptive neurons without affecting the remaining four neurons (5.5%). The statistical comparison on a bin-by-bin basis of the peri-R wave interval histograms of the discharge of each NTS neuron showed that the inhibitory action of muscimol was always exerted on the whole neuronal discharge independently of its correlation to the cardiac cycle. Baclofen inhibited 60 of 73 (82.2%) NTS neurons without affecting the remaining 13 neurons (17.8%). In 31 of 60 (51.7%) neurons inhibited by baclofen, this substance significantly affected only pulse-synchronous peaks of neuronal discharge without significant inhibition of the neuronal firing between cardiac cycle-related peaks. Fifty-eight of 73 (79.5%) NTS neurons studied were inhibited by both muscimol and baclofen, 11 neurons (15%) only by muscimol, 2 neurons (2.7%) only by baclofen, and 2 neurons (2.7%) were unaffected by both substances. These results demonstrate that both GABAA and GABAB receptors mediate inhibition of the spontaneous discharge in the great majority of the NTS baroreceptive neurons studied and suggest different functions of the two types of GABA receptors in influencing baroreceptor inputs to the NTS.
Article
Single units in the medial subnucleus of the nucleus tractus solitarii, responding to electrical stimulation of subdiaphragmatic vagal fibers, were recorded extracellularly in an in vitro neonatal rat brainstem-gastric preparation. Selective opioid receptor agonists were applied only to the gastric compartment of the bath chamber and therefore, the brainstem functions of the preparation were not affected. The peripheral gastric effects of the mu-opioid receptor agonist, [D-Ala2, N-MePhe4, Gly5-ol]enkephalin (DAMGO) and kappa-opioid receptor agonist, ¿trans-3,4-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]cyclohexyl] benzeneacetamide methanesulfonate hydrate¿ (U-50, 488H), were evaluated on 69 units that received the subdiaphragmatic vagal input. For approximately 75% of the units observed, DAMGO (1.0 microM; IC70; 80 nM) and U-50, 488H (1.0 microM; IC70:200 nM) induced a concentration-dependent inhibition of 62.7 +/- 8.9% (mean +/- S.D.) and 50.6 +/- 6.2% of the control level of the brainstem neuronal activity, respectively. The mu-opioid selective receptor antagonist, naltrexone and non-selective opioid receptor antagonist, naloxone, respectively, blocked the inhibitory effects by DAMGO and U-50, 488 H. The delta-opioid receptor agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE) (10 microM; IC70:400 nM) produced a lesser extent of inhibition of 21.9 +/- 8.0% in the only 10 out of 51 (20%) neurons tested, and this effect was blocked by naloxone. The area of the stomach where gastric opioid receptors contributed most to brainstem unitary activity was also examined. This was achieved by comparing the opioid effects on a whole-stomach preparation to its effects on a partial-stomach preparation. Our data indicated that the distal stomach containing the pylorus played a key role in the gastric effects of mu- and kappa-opioid receptors on brainstem neuronal activity. These results suggest that the mu- and kappa-opioid receptors of the distal stomach are important in modulation of brainstem neuronal activity and may play a role in regulating the digestive process.
Article
To review the epidemiology, etiology, and classification of insomnia and provide an overview of the pharmacologic therapy of insomnia. Novel nonbenzodiazepine hypnotics including zolpidem, zopiclone, and zaleplon, as well as nonprescription products such as valerian and melatonin, are reviewed in detail. A MEDLINE search was performed to identify relevant clinical studies, case reports, abstracts, and review articles published between April 1992 and December 1997. Key search terms included insomnia, benzodiazepines, zolpidem, zopiclone, zaleplon, Cl 284,846, melatonin, and valerian. Additional references were obtained from the lists of review articles and textbooks. Data concerning the safety and efficacy of the hypnotic agents were extracted from all available clinical trials and abstracts. Background information regarding insomnia, benzodiazepines, and other hypnotics was extracted from the most current literature, including review articles and textbooks. New developments in benzodiazepine receptor pharmacology have introduced novel nonbenzodiazepine hypnotics that provide comparable efficacy to benzodiazepines. Although they may possess theoretical advantages over benzodiazepines based on their unique pharmacologic profiles, they offer few, if any, significant advantages in terms of adverse effects. Over-the-counter agents such as valerian and melatonin may be useful in alleviating mild, short-term insomnia, but further clinical trials are required to fully evaluate their safety and efficacy.
Article
Single units in the region of the medial nucleus tractus solitarius (NTS), responding to electrical stimulation of gastric vagal fibers, were recorded in an in vitro neonatal rat brainstem-gastric preparation. gamma-Aminobutyric acid (GABA) subreceptor agonists and antagonists were applied to the gastric and brainstem compartments of the bath chamber to evaluate the peripheral gastric and central brainstem GABAergic effects on NTS neuronal activity. The gastric effects of the GABAA receptor agonist muscimol and GABAB receptor agonist baclofen were evaluated on 55 tonic units that received the gastric vagal inputs. For approximately 58% (32 of 55) and 38% (21 of 55) of the units observed, muscimol (30 microM; IC50 = 2.0 microM) and baclofen (30 microM; IC50 = 1.5 microM) in the gastric compartment induced a concentration-dependent inhibition of 36.2 +/- 3.1% (mean +/- S.E.) and 31.0 +/- 2.9% of the control level of the NTS neuronal activity, respectively. The brainstem effects of muscimol and baclofen were tested on 51 units. For approximately 90% (46 of 51) and 78% (40 of 51) of the units tested, muscimol (30 microM; IC50 = 1.3 microM) and baclofen (30 microM; IC50 = 1.1 microM) in the brainstem compartment produced a concentration-dependent inhibition of 54.1 +/- 3.4% and 48.9 +/- 3. 5% of the control level, respectively. The remaining NTS units were not affected by these two GABA agonists. Bicuculline (10 microM) and saclofen (10 microM), the GABAA and GABAB subreceptor antagonists, competitively antagonized the gastric and brainstem effects by muscimol and baclofen, respectively. Our results demonstrated that both GABAA and GABAB receptors in the stomach and brainstem play an important role in activity modulation of the medial NTS neurons receiving gastric vagal inputs in neonatal rats.
Article
The underground organs of members of the genus Valeriana (Valerianaceae), as well as related genera such as Nardostachys, are used in the traditional medicine of many cultures as mild sedatives and tranquillizers and to aid the induction of sleep. V. officinalis is the species most commonly used in northern Europe and still retains its official pharmaco-poeial status although it is most commonly encountered as an ingredient of herbal medicines. This plant is still the subject of considerable research aimed at establishing the chemical and pharmacological basis of the activity which has been clearly shown in a number of animal and clinical studies. The constituents of the volatile oil are very variable due to population differences in genetics and to environmental factors. The major constituents include the monoterpene bornyl acetate and the sesquiterpene valerenic acid, which is characteristic of the species, in addition to other types of sesquiterpene. Some of these have been shown to have a direct action on the amygdaloid body of the brain and valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain resulting in sedation. The non-volatile monoterpenes known as valepotriates were first isolated in 1966 and contribute to the overall activity by possessing sedative activity based on the CNS although the mode of action is not clearly known. The valepotriates themselves act as prodrugs which are transformed into homobaldrinal which has been shown to reduce the spontaneous motility of mice. More recent studies have shown that aqueous extracts of the roots contain appreciable amounts of GABA which could directly cause sedation but there is some controversy surrounding the bioavailability of this compound. Another recent finding is the presence of a lignan, hydroxypinoresinol, and its ability to bind to benzodiazepine receptors. Valerian is a good example of both the negative and positive aspects of herbal drugs. The considerable variation in its composition and content as well as the instability of some of its constituents pose serious problems for standardization but the range of components which contribute to its overall activity suggest that it may correct a variety of underlying causes of conditions which necessitate a general sedative or tranquillizing effect.
Article
Objective: To systematically review the evidence for the effects of the herb valerian (Valeriana officinalis) on insomnia, based on randomized, placebo-controlled, double-blind trials.Background: Valerian has long been advocated and used for promoting sleep but until quite recently evidence was solely anecdotal. However, during the last two decades a number of clinical trials have been conducted.Materials and methods: Systematic literature searches were performed to locate randomized, placebo-controlled, double-blind trials measuring the effect of valerian monopreparations on sleep in human participants. Data were extracted in a standardized manner and methodological quality was assessed by the Jadad score.Results: Nine trials were located meeting the selection criteria. The findings of the studies were contradictory and there was great inconsistency between trials in terms of patients, experimental design and procedures and methodological quality.Conclusion: The evidence for valerian as a treatment for insomnia is inconclusive. There is a need for rigorous trials to determine its efficacy.
Article
Insomnia is the most common sleep disorder, and is often associated with significant medical, psychological, and social disturbances. Conventional medical treatment for insomnia includes psychological and pharmacological approaches; however, long-term use of frequently prescribed medications can lead to habituation and problematic withdrawal symptoms. Therefore, herbal and other natural sleep aids are gaining popularity, as herbs commonly used for their sedative-hypnotic effects do not have the drawbacks of conventional drugs. Whether alternative therapies possess activity similar to conventional therapies needs further evaluation.
Article
In the present study we evaluated the effects of bilateral microinjection of muscimol (a GABA(A) receptor agonist) and baclofen (a GABA(B) receptor agonist) into the lateral commissural nucleus tractus solitarii (NTS) of awake rats on the gain of the baroreflex (BG) activated by a short duration (10-15 s) infusion of phenylephrine (Phe, 2.5 μg/0.05 ml, i.v.). Microinjection of muscimol (50 pmol/50 nl, n = 8) into the NTS produced a significant increase in baseline mean arterial pressure ((MAP) 122 ± 6 vs. 101 ± 2 mmHg), no changes in baseline heart rate (HR) and a reduction in BG (-1.59 ± 0.1 vs. -0.69 ± 0.1 beats/mmHg). Microinjection of baclofen (6.25 pmol/50 nl, n = 6) into the NTS also produced a significant increase in baseline MAP (138 ± 5 vs. 103 ± 2 mmHg), no changes in baseline HR and a reduction in BG (-1.54 ± 0.3 vs. -0.53 ± 0.2 beats/mmHg). Considering that the reduction in BG could be secondary to the increase in MAP in response to microinjection of muscimol (n = 6) or baclofen (n = 7) into the NTS, in these two groups of rats we brought the MAP back to baseline by infusion of sodium nitroprusside (NP, 3.0 μg/0.05 ml, i.v.). Under these conditions, we verified that the BG remained significantly reduced after muscimol (-1.49 ± 0.2 vs. -0.35 ± 0.2 beats/mmHg) and after baclofen (-1.72 ± 0.2 vs. -0.33 ± 0.2 beats/mmHg) when compared to control. Reflex tachycardia was observed during the normalization of MAP by NP infusion and, in order to prevent the autonomic imbalance from affecting BG, we used another group of rats treated with atenolol (5 mg/kg, i.v.), a β1 receptor antagonist. In rats previously treated with atenolol and submitted to NP infusion, we verified that BG remained reduced after microinjection of muscimol or baclofen into the NTS. The data show that activation of GABA(A) and GABA(B) receptors, independently of the changes in the baseline MAP or HR, inhibited the neurons of the NTS involved in the parasympathetic component of the baroreflex.
Article
Expression of mRNAs encoding seven GABA(A) receptor subunits (alpha1, alpha2, alpha3, alpha5, beta2, beta3, gamma2) in the nucleus tractus solitarii (NTS) of rat medulla oblongata was examined by reverse transcription-polymerase chain reaction (RT-PCR). All subunit mRNAs, except alpha5, were clearly detected. Band densities produced by alpha1, alpha3, beta3, and gamma2 subunits were greater than those corresponding to beta2 and alpha2 transcripts. The localization of these subunits in tissue sections through NTS was examined by immunohistochemistry. The differential patterns of immunoreactivity in neuronal somata and dendrites of NTS neurons were generally in agreement with the PCR results, confirming that mRNA expression is correlated with receptor protein synthesis. At ultrastructural level, alpha1, alpha3, beta2/3, and gamma2 subunits were localized in both cytoplasmic and subsynaptic sites, the latter often apposed to GABA immunoreactive synapses. These results suggest that ionotropic receptors comprising the alpha1, alpha3, beta2/3, and gamma2 may mediate inhibitory GABA responses in the NTS.
Article
Widespread use of herbal medications among the presurgical population may have a negative impact on perioperative patient care. To review the literature on commonly used herbal medications in the context of the perioperative period and provide rational strategies for managing their preoperative use. The MEDLINE and Cochrane Collaboration databases were searched for articles published between January 1966 and December 2000 using the search terms herbal medicine, phytotherapy, and alternative medicine and the names of the 16 most commonly used herbal medications. Additional data sources were obtained from manual searches of recent journal articles and textbooks. We selected studies, case reports, and reviews addressing the safety and pharmacology of 8 commonly used herbal medications for which safety information pertinent to the perioperative period was available. We extracted safety, pharmacodynamic, and pharmacokinetic information from the selected literature and reached consensus about any discrepancies. Echinacea, ephedra, garlic, ginkgo, ginseng, kava, St John's wort, and valerian are commonly used herbal medications that may pose a concern during the perioperative period. Complications can arise from these herbs' direct and pharmacodynamic or pharmacokinetic effects. Direct effects include bleeding from garlic, ginkgo, and ginseng; cardiovascular instability from ephedra; and hypoglycemia from ginseng. Pharmacodynamic herb-drug interactions include potentiation of the sedative effect of anesthetics by kava and valerian. Pharmacokinetic herb-drug interactions include increased metabolism of many drugs used in the perioperative period by St John's wort. During the preoperative evaluation, physicians should explicitly elicit and document a history of herbal medication use. Physicians should be familiar with the potential perioperative effects of the commonly used herbal medications to prevent, recognize, and treat potentially serious problems associated with their use and discontinuation.
Article
Using the guidance by a competitive assay for the benzodiazepine binding site in the GABAA receptor, active compounds were isolated from the rhizomes and roots of Valeriana wallichii DC. The UV, NMR and mass spectral data permitted the identification of 6-methylapigenin. This flavonoid has a Ki = 495 nM for the BDZ-bs and a GABA ratio of 1.6 - 2.0, which suggests possible agonistic properties. The calculated percentage of 6-methylapigenin in the crude drug is in the range: 0.013 % to 0.0013 %. Abbreviations BDZ-bs:benzodiazepine binding site GABA ratio:gamma amino butyric acid ratio GABAA:gamma amino butyric acid type A receptor ³H-FNZ:tritium flunitrazepam Ki:inhibition constant
Article
A methanolic extract of the roots of Valeriana officinalis (valerian) was investigated for its lignan content. In addition to the lignans 8'-hydroxypinoresinol (1) and pinoresinol-4-O-beta-D-glucoside (2), which had already been isolated from valerian in an earlier study, the 7,9'-monoepoxylignans massoniresinol-4'-O-beta-D-glucoside (3), 4'-O-beta-D-glucosyl-9-O-(6' '-deoxysaccharosyl)olivil (4), and berchemol-4'-O-beta-D-glucoside (5) and the 7,9':7',9-diepoxylignans pinoresinol-4,4'-di-beta-O-D-glucoside (6), 8-hydroxypinoresinol-4'-O-beta-D-glucoside (7), and 8'-hydroxypinoresinol-4'-O-beta-D-glucoside (8) were identified. While lignans 3, 6, 7, and 8 had already been isolated from other plants, lignans 4 and 5 are new natural products. The lignans were investigated in radioligand binding assays at various receptors of the central nervous system, including GABA(A), benzodiazepine, 5-HT(1A), and adenosine A(1) and A(2A) receptors, to investigate their potential contribution to the pharmacological activity of valerian. The novel olivil derivative 4 proved to be a partial agonist at rat and human A(1) adenosine receptors exhibiting A(1) affinity and activity in low micromolar to submicromolar concentrations. Lignan 4 is the first nonnucleoside adenosine receptor agonist not structurally related to adenosine.
Article
Using an in vitro neonatal rat gastric-brainstem preparation, the activity of majority neurons recorded in the nucleus tractus solitarius (NTS) of the brainstem were significantly inhibited by GABA A receptor agonist, muscimol (30 microM), and this inhibition was reversed by selective GABA A receptor antagonist, bicuculline (10 microM). Application of kavalactones (300 microg/ml) and dihydrokavain (300 microM) into the brainstem compartment of the preparation also significantly reduced the discharge rate of these NTS neurons (39 % and 32 %, respectively, compared to the control level), and this reduction was partially reversed by bicuculline (10 microM). Kavalactones or dihydrokavain induced inhibitory effects were not reduced after co-application of saclofen (10 microM; a selective GABA B receptor antagonist) or naloxone (100 nM; an opioid receptor antagonist). Pretreatment with kavalactones (300 microg/ml) or dihydrokavain (300 microM) significantly decreased the NTS inhibitory effects induced by muscimol (30 microM), approximately from 51 % to 36 %. Our results demonstrated modulation of brainstem GABAergic mechanism by kavalactones and dihydrokavain, and suggested that these compounds may play an important role in regulation of GABAergic neurotransmission.
Article
A group of 8 volunteers suffering from mild insomnia received a placebo, 450 mg or 900 mg of an aqueous extract of valerian root in a double-blind, repeated measures, random-order design. Subjective sleep ratings were assessed by questionnaire and movements were recorded throughout the night with wrist-worn activity meters. Using the first period of 5 consecutive minutes without movement as a criterion of sleep onset, there was a significant decrease in sleep latency with 450 mg valerian compared to placebo (15.8 +/- 2.2 min vs 9.0 +/- 1.5 min; paired "t" = 3.37;p < 0.01). The higher dose of valerian produced no further improvement in sleep latency.
Article
Valerenic acid, isolated from VALERIANA OFFICINALIS L. s.l. affected the rotarod and traction performance of mice in a similar manner to that of pentobarbital which was used together with chlorpromazine and diazcpam as reference substance in both tests. A decrease of locomotility of mice was also noticed after administration of valerenic acid, in particular when this compound was administered to the same group of mice a week later than the vehicle. In addition valerenic acid was found to prolong the pentobarbital induced sleeping time. It can be concluded, that valerenic acid has aspecific central nervous depressent properties. This factor should be taken into account when considering the sedative action of Valerian preparations.
  • Anesth Analg
  • Anesthetic Yuan
  • Al
ANESTH ANALG ANESTHETIC PHARMACOLOGY YUAN ET AL. 2004;98:353–8 GABAERGIC EFFECTS OF VALERIAN ON THE BRAINSTEM
  • S Russmann
  • Bh Lauterburg
  • A Helbling
  • Kava Hepatotoxicity
Russmann S, Lauterburg BH, Helbling A. Kava hepatotoxicity. Ann Intern Med 2001;35:68 –9.
Most commonly used herbal medicines in the U Textbook of complementary and alternative medicine