Among 150 potentially active phytochemicals, constituents identified in the Valerian's roots are (1) iridoid valepotriates (0.5%–2.0%): valtrate, isovaltrate, didrovaltrate, acevaltrate and others and (2) volatile essential oil (0.2%–2.8%) divided in (a) monoterpenes: borneol and bornyl acetate and (b) sesquiterpenes: valerenic, valeric, isovaleric and acetoxyvalerenic acids: valerenal, valeranone, and kessyl glycol [14
]. Some sesquiterpenes, such valerenic acid, influence serotonin and noradrenaline levels, reduce locomotion, and anxiety, and increase pentobarbital sleeping time of mice [16
]. Similarly, other constituents, such as valepotriates potentiate hexobarbital anesthesia, suppress aggression, have anticonvulsant effects against pentylenetetrazole- and strychnine-induced seizures, increase thiopental sleeping time, reduce motility, and have dose-dependent sedative effects [17
]. In addition, valepotriates and their decomposition products, baldrinals and homobaldrinals, reduced the total HAM-A (Hamilton anxiety scale) in a small clinical trial [20
] and increased the time spent in open arms when elevated plus maze test was performed in rats [19
]. Therefore, it is most likely that valerian's pharmacological properties are due to the additive effects of multiple active constituents and not one alone [21
Most of the Valerian effects described above are consistent with the enhancement of GABAa-mediated transmission [7
]. Cavadas and colleagues showed that valerian extracts bind to GABAa
], while other researchers found that valerian is a partial agonist of the 5-HT(5a) receptor [8
] and promotes cell proliferation in the hippocampus of “depressive” rats [25
]. Moreover, recent studies suggest that different components within the valerian extract mediate the activation of adenosine receptors [26
]. Indeed, many studies have been done to determine the interaction of valerian with different receptors, but none of them examined valerian-glutamate receptor interaction.
H]Glutamate displacement curve in presence of Valeriana officinalis
demonstrated that valerian extracts increase glutamate binding from 8 × 10−7
to 1 × 10−1
mg/mL reaching a maximum 3
[H]Glutamate binding at 1 × 10−3
mg/mL (160%). Therefore, at these physiological attainable concentrations (8 × 10−7
–1 × 10−1
mg/mL) valerian potentiates 3
[H]Glutamate binding. In contrast, different findings were obtained for valerenic acid and isoborneol. The [3
H]Glutamate displacement curves and the receptor selectivity obtained for valerian and its constituents, for instance, are very different from each other, suggesting that these constituents are not the compounds responsible for the increase in 3
[H]Glutamate binding observed with valerian.
The glutamatergic system plays an important role in anxiety pathogenesis [28
]. It is suggested that the physiological and behavioral responses associated with anxiety are regulated by a balance between the inhibition produced by GABA and the excitation caused by glutamate. Treatments used to decrease excitability in neurons from the amygdala are achieved by increasing GABA neurotransmission. Alternatively, treatments to decrease the excitability can be obtained by decreasing the excitatory glutamatergic transmission. Therefore, decreasing excitatory neurotransmission in the CNS, by modulating the response produced by the glutamatergic receptors, is an alternative approach to produce anxiolysis and sedation. The glutamate receptors found in the amygdala produce excitatory and inhibitory actions, and the degree of ionotropic and metabotropic activation is an important factor to determine the amygdala cell excitability. Thus, the modulation of glutamate actions mediated by iGluR and mGluR represent a feasible alternative to treat anxiety states [12
Compounds that decrease glutamatergic transmission via blockade of NMDA have been reported to produce anxiolytic and antidepressant like actions in animal tests and models [30
]. Our group demonstrated that valerian extract had modest inhibitory effects on [3
H]MK-801 binding, an indicator of NMDA-valerian interaction [32
]. In 2004, Malva and colleagues reported that by decreasing neuronal network excitability through AMPA permeable Ca2+
receptors, valerian preparations could contribute to neuroprotection and may be of therapeutic use in preventing glutamate-mediated degeneration related to aging or neurodegenerative disorders [33
]. Now, our study confirms that in the presence of iGluR agonists, valerian extracts interact with KA and NMDA (0.05
mg/mL and 10
mg/mL, resp.). While isoborneol exhibited significant interactions with all iGluR, valerenic acid did not interact with iGluR agonists.
Many studies suggest that metabotropic glutamate receptors are involved in anxiety [12
]. For this reason, we performed receptor-binding assays with valerian extracts in presence of different types of metabotropic glutamate receptors. In this study, we demonstrated that valerian extracts, in presence of mGluR ligands, exhibited significant interaction with QA (Group I mGluR) and LCCG-I (Group II mGluR). Valerenic acid selectively interacts with QA. However, isoborneol interacts with all mGluR receptors. Our results clearly demonstrated that Valeriana offiicinalis
and it constituents (valerenic acid and isoborneol) interact with Group I and II mGluR, which supports previous studies showing the role of Group I and II mGluR in anxiety [35
The pharmacological effects of Valeriana officinalis extracts in [3H]Glutamate binding are not conventional and easy to understand. They could reflect complex interactions (agonist/antagonist) or synergism occurring in the complex mixture of phytochemical constituents. The biphasic [3H]Glutamate displacement curve obtained in presence of valerian represents an example of the interactions that occur in an extract which could not be evident when single constituents are studied in isolation. This study exclusively used receptor-binding assays to determine ligand-receptor interactions, but functionalities studies are being conducted to characterize them.
Our results confirm the hypothesis of valerian interaction with the glutamatergic receptors, suggesting a possible mechanism by which valerian extracts produce their effects. Val-mGluR interactions may represent a novel alternative for the treatment of anxiety. Further studies with fractions of valerian extract should be done to evaluate the interactions between a group of compounds and their effects on receptor-binding selectivity.