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Central nervous system effects of natural and synthetic flavonoids
Abstract
Flavonoids are naturally occurring molecules present in the human diet. We demonstrate that some flavonoids possess central nervous system effects, acting through the central benzodiazepine receptors. The pharmacological characterization of chrysin (5,7-dihydroxyflavone) and apigenin (5,7,4′-trihydroxyflavone), isolated from Passiflora coerulea and Matricaria recutita, respectively, showed their anxiolytic, but not myorelaxant or amnesic effects. Cirsiliol (5,3′,4′-trihydroxy-6,7-dimethoxyflavone), however, isolated from Salvia guaranitica, had sedative-depressant properties. We were able to increase the biochemical and pharmacological potency of the natural flavonoids by means of the addition of halo and/or nitro groups to the flavone nucleus. Some flavonoids are partial agonists of the benzodiazepine receptors and may become new therapeutic drugs, devoid of the unwanted side effects of classical benzodiazepines.
... Recently a new chromone, 5,6-dihydroxy-2-methyl chromone along with seven known flavonoids have been isolated from the leaves of F. lyrata (Omer et al., 2005). The pharmacological effects of the flavonoids on the central nervous system have been explored earlier (Karaay et al., 2007;Viola et al., 1998;Sebastian et al., 2006). ...
The crude aqueous and alcoholic extracts of the leaves of Ficus lyrata have been investigated for possible analgesic activity and central depressor activity. The crude aqueous and alcoholic extracts at a dose of 200 mg/kg each showed significant analgesic activity by Analgesiometer test. Both extracts in the same doses also showed central depressor activity by open field behaviour test.
... Furthermore, they showed that flumazenil (1 mM) was able to antagonise the inhibitory effect of apigenin (1-10 mM) on the action of GABA on cultured cerebellar granule cells. In contrast to other studies (Viola et al., 1995;Salgueiro et al., 1997;Viola et al., 1998), Avallone and colleagues were unable to observe any anxiolytic action of apigenin . They concluded that 'the sedative action of apigenin cannot be ascribed to an activation of GABAA receptors' . ...
There has been a resurgence of interest in synthetic and plant-derived flavonoids as modulators of γ-amino butyric acid-A (GABA(A) ) receptor function influencing inhibition mediated by the major inhibitory neurotransmitter GABA in the brain. Areas of interest include (i) flavonoids that show subtype selectivity in recombinant receptor studies in vitro consistent with their behavioural effects in vivo, (ii) flumazenil-insensitive modulation of GABA(A) receptor function by flavonoids, (iii) the ability of some flavonoids to act as second-order modulators of first-order modulation by benzodiazepines and (iv) the identification of the different sites of action of flavonoids on GABA(A) receptor complexes. An emerging area of interest is the activation of GABA(A) receptors by flavonoids in the absence of GABA. The relatively rigid shape of flavonoids means that they are useful scaffolds for the design of new therapeutic agents. Like steroids, flavonoids have wide-ranging effects on numerous biological targets. The challenge is to understand the structural determinants of flavonoid effects on particular targets and to develop agents specific for these targets.
... Cirsimaritin was reported to have a high anti-microbial activity against several bacteria strains (Miski et al., 1983) while hispidulin possessed antihepatotoxic activity (Oshima et al., 1984). In a more recent report (Viola et al., 1998), the sedativedepressant property for cirsiliol was described. ...
Salvia is an important genus widely cultivated and used in flavouring and folk medicines. The genus has attracted great interest so much so that it has been the subject of numerous chemical studies. It is a rich source of polyphenols, with an excess of 160 polyphenols having been identified, some of which are unique to the genus. A large number of these polyphenolic compounds are apparently constructed from the caffeic acid building block via a variety of condensation reactions. The nature of these polyphenols which have been reported is compiled in this report together with some bioactivity data in an effort to show the rapid development in the phytochemistry and the therapeutic applications of the Salvia species.
The essential oil of aerial parts of Salvia guaranitica, grown in a small-scale experimental field in Uruguay, was analysed by GC, GC–MS and 13C-NMR; 49 constituents (86.6% of the total sample) were identified. The major components were found to be sesquiterpene hydrocarbons: germacrene D (25.0%), β-elemene (20.0%), β-caryophyllene (8.8%) and β-bourbonene (6.2%), whereas monoterpenes only reached 4% of the sample analysed. Copyright © 2005 John Wiley & Sons, Ltd.
Passiflora incarnata Linn. has been used to cure anxiety and insomnia since time immemorial. Despite the worldwide use of P. incarnata, the pharmacological work on this plant had been inadequate, inconclusive and wage as the earlier reports were unable to infer the mode of action of the plant as well as the phytoconstituents responsible for the much acclaimed anxiolytic and sedative effects of P. incarnata. An attempt has been made to isolate and identify the bioactive phytomoiety of P. incarnata by resorting to bioactivity directed fractionation and chromatographic procedures. A fraction derived from the methanol extract of P. incarnata has been observed to exhibit significant anxiolytic activity at a dose of 10 mg/kg in mice using elevated plus-maze model of anxiety. This fraction comprises mainly two components which are visible as blue and turquoise colored fluorescent spots at 366 nm of the UV light. The possibility of a phytoconstituent having benzoflavone nucleus as the basic moiety being responsible for the bioactivity of P. incarnata is highly anticipated.
The present work is a mini-review of the author's original work on the plant Passiflora incarnata Linn., which is used in several parts of the world as a traditional medicine for the management of anxiety, insomnia, epilepsy and morphine addiction. A tri-substituted benzoflavone moiety (BZF) has been isolated from the bioactive methanol extract of this plant, which has been proposed in the author's earlier work to be responsible for the biological activities of this plant. The BZF moiety has exhibited significantly encouraging results in the reversal of tolerance and dependence of several addiction-prone psychotropic drugs, including morphine, nicotine, ethanol, diazepam and delta-9-tetrahydrocannabinol, during earlier pharmacological studies conducted by the author. In addition to this, the BZF moiety has exhibited aphrodisiac, libido-enhancing and virility-enhancing properties in 2-year-old male rats. When administered concomitantly with nicotine, ethanol and delta-9-tetrahydrocannabinol for 30 days in male rats, the BZF also prevented the drug-induced decline in sexuality in male rats. Because the BZF moiety isolated from P. incarnata is a tri-substituted derivative of alpha-naphthoflavone (7,8-benzoflavone), a well-known aromatase-enzyme inhibitor, the mode of action of BZF has been postulated to be a neurosteroidal mechanism vide in which the BZF moiety prevents the metabolic degradation of testosterone and upregulates blood - testosterone levels in the body. As several flavonoids (e.g. chrysin, apigenin) and other phytoconstituents also possess aromatase-inhibiting properties, and the IC50 value of such phytomoieties is the main factor determining their biochemical efficacy, by altering their chemical structures to attain a desirable IC50 value new insights in medical therapeutics can be attained, keeping in view the menace of drug abuse worldwide.
This review describes the morphology, microscopy, traditional and folklore uses, phyto-constituents, pharmacological reports, clinical applications and toxicological reports of the prominent species of the genus Passiflora. Flavonoids, glycosides, alkaloids, phenolic compounds and volatile constituents have been reported as the major phyto-constituents of the Passiflora species. A few species of Passiflora have been used for curing various ailments, the most important being Passiflora incarnata Linneaus which possesses significant CNS depressant properties. The studies performed by the authors with the newly isolated benzoflavone (BZF) moiety from P. incarnata have been discussed. In the concluding part, various virgin areas of research on the species of this genus have been highlighted with a view to explore, isolate and identify the medicinally important phyto-constituents which could be utilized to alleviate various diseases affecting the mankind.
6,3'-Dinitroflavone (2) and 6,4'-dinitroflavone (3), prepared by direct nitration of flavone (1), were found to be ligands for the benzodiazepine receptor (BDZ-R). Compound 2, with a Ki= 12 nM, produced potent anxiolytic effects in mice at a dose of 1 μg/Kg.
The synthesis and biochemical characterization of 6-bromo-3′-nitroflavone (1) is presented. Compound 1 has higher affinity for cerebellar and cerebral cortical than for striatal, hippocampal, or spinal cord benzodiazepine receptors (BDZ-Rs). In the cerebral cortex it recognizes two populations of binding sites (Kis 1.2 nM and 15.5 nM, respectively), and at doses of 0.01 to 0.3 mg/kg, ip produces anxiolytic effects in mice.
The psychopharmacological profile of quercetin (Q) and penta-O-ethylquercetin (PQ) showed for both compounds a sedative effect on central nervous system in mice. In this set of pharmacological tests (hypothermia, spontaneous motility, psychomotor activity) penta-O-ethylquercetin always exerted a more pronounced effect than quercetin, probably due to the difference of lipophilicity. In analgesia experiments such as acetic acid-induced writhings, penta-O-ethylquercetin showed a significant dose-related effect whereas quercetin was inactive. As pretreatment with naloxone failed to antagonize the analgesic activity of penta-O-ethylquercetin, it was suggested that penta-O-ethylquercetin acted mainly peripherally.
Using modern techniques, we now find ourselves closer to understanding more clearly the complexity of GABAA receptor function. Heterogeneity of the GABAA receptor family has been shown to exist while its significance in the regulation of cell function continues to be evaluated. In closing, it must be said many contributions which brought us to our current understanding of the GABAA receptor are attributed to the combined efforts of Dr. Erminio Costa and his laboratories. Through many years of dedicated work and perseverance, he and his co-workers have helped to move the neuroscience community rapidly forward. His efforts continue to influence and inspire creative scientific thinking and research development in neuroscience.
Alpidem, an imidazo-pyridine compound, has been evaluated as an anxiolytic in comparison with placebo and lorazepam. In the first of our normal volunteer studies, we compared single doses of alpidem, 25, 50 and 100 mg with lorazepam 2 mg and placebo on a range of cognitive, psychomotor and EEG variables. Lorazepam and the highest (100 mg) dose of alpidem impaired performance on a range of psychomotor tasks, the effects of the benzodiazepine being more severe and more prolonged. No impairment of performance was observed with the 25 and 50 mg doses.
In the second study, the focus was on memory functions. Lorazepam, 2 mg, caused anterograde amnesia which was most apparent 1 h post-drug but persisted until 4 h: sedation was marked. By contrast, single doses (25, 50 mg) of alpidem had little effect on either memory or alertness.
The third study compared the effects of alpidem (25, 50 mg) and lorazepam (1 mg) with placebo, each given twice-daily for 8 days to normal volunteers. On the final day, a test dose of ethanol was given. Lorazepam impaired many tests of cognitive and psychomotor function, and this impairment was enhanced by ethanol. By contrast, alpidem produced less impairment with less interaction with alcohol.
In a fourth, clinical, study, 24 patients with a DSM III primary diagnosis of generalised anxiety disorder were treated, under double blind conditions, with doses adjusted according to clinical need of either alpidem 25 - 150 mg daily or lorazepam 1 - 6 mg daily. Alpidem was an effective anxiolytic producing no significant withdrawal syndrome after 4 weeks use in contrast to the problems encountered in using the comparison drug lorazepam. Physiological and psychological effects were similar to those of our normal subject studies.
Continuous administration of triazolam, alprazolam or diazepam for a 7-day period by means of minipumps or chronic (17 days) p.o. treatment with alprazolam induced clear physical dependence in DBA/2J mice as assessed by precipitation of a withdrawal syndrome with an i.v. injection of the benzodiazepine receptor partial inverse agonist Ro 15-3505. In contrast, no precipitated withdrawal signs were observed following chronic exposure to high doses of the benzodiazepine receptor partial agonist Ro 16-6028. The use of minipumps and precipitation with a benzodiazepine receptor antagonist permits a simple and rapid evaluation of the physical dependence liability of potent compounds acting at the benzodiazepine receptor. Furthermore, these results support the hypothesis that benzodiazepine receptor partial agonists are less likely to induce physical dependence than full agonists.
In a search for pharmacologically-active ingredients in the plant extract Karmelitter Geist, we have isolated and identified a high-affinity benzodiazepine receptor ligand, amentoflavon. Amentoflavon binds in a mix-type competitive and non-competitive manner to brain benzodiazepine receptors with an IC50-value of 6 nM in vitro, comparable to the affinity of diazepam. Amentoflavon shows a GABA ratio of 1.4 at 0 degrees and increases 35S-TBPS binding by 12% (60 min incubation at 25 degrees), which indicates a partial agonistic effect on benzodiazepine receptors. The substance does not influence the binding of a variety of other brain receptor ligands. Amentoflavon does not inhibit 3H-flunitrazepam-binding to brain benzodiazepine receptors following i.v. administration in the mouse in vivo, and it is therefore not likely that amentoflavon is responsible for any pharmacological effect of Karmelitter Geist.
The dried flower heads of Matricaria recutita L. (Asteraceae) are used in folk medicine to prepare a spasmolytic and sedative tea. Our fractionation of the aqueous extract of this plant led to the detection of several fractions with significant affinity for the central benzodiazepine receptor and to the isolation and identification of 5,7,4'-trihydroxyflavone (apigenin) in one of them. Apigenin competitively inhibited the binding of flunitrazepam with a Ki of 4 microM and had no effect on muscarinic receptors, alpha 1-adrenoceptors, and on the binding of muscimol to GABAA receptors. Apigenin had a clear anxiolytic activity in mice in the elevated plusmaze without evidencing sedation or muscle relaxant effects at doses similar to those used for classical benzodiazepines and no anticonvulsant action was detected. However, a 10-fold increase in dosage produced a mild sedative effect since a 26% reduction in ambulatory locomotor activity and a 35% decrement in hole-board parameters were evident. The results reported in this paper demonstrate that apigenin is a ligand for the central benzodiazepine receptors exerting anxiolytic and slight sedative effects but not being anticonvulsant or myorelaxant.
Alpidem is a new anxiolytic of imidazopyridine structure which has a high affinity for the omega 1 (BZ1) modulatory site of the GABAA receptor. The present study investigated whether tolerance and physical dependence develop after repeated treatment with alpidem, as is observed with benzodiazepines. Mice were given alpidem (100 mg/kg, p.o.) or diazepam (5 mg/kg, p.o.) twice daily for 10 consecutive days. Tolerance was assessed by measuring antagonism of pentylenetetrazole- and isoniazid-induced convulsions and bicuculline-provoked mortality, following repeated drug treatment. Decreases in the latency to isoniazid-induced convulsions and in the minimal convulsant dose of pentylenetetrazole were taken as an index of physical dependence and were evaluated at different times (3, 6, 14, 42, 67, 96 hr) after drug withdrawal or after flumazenil administration. In addition, changes in sensitivity to the convulsant effect of a beta-carboline (beta-CCM) were measured. Repeated treatment with diazepam produced tolerance to its anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3-5. After discontinuation of diazepam treatment, spontaneous withdrawal occurred within 24 hr and lasted 67 hr as indicated by decreases in the threshold for convulsions induced by isoniazid and pentylenetetrazole. Flumazenil-induced withdrawal was observed in both isoniazid and pentylenetetrazole-induced convulsion models. Hypersensitivity of mice to the convulsant effect of beta-CCM also occurred. In contrast, repeated treatment with alpidem did not produce tolerance to its anticonvulsant effects and neither spontaneous nor flumazenil-induced withdrawal was observed in the pentylenetetrazole and isoniazid models. Moreover, withdrawal of alpidem did not induce any change in the convulsant activity of beta-CCM. These differences between alpidem and diazepam may be related to the low level of receptor occupancy during repeated treatment with alpidem because of its selectivity for omega 1 (BZ1) sites and to its moderate intrinsic activity.
Tilia species are traditional medicinal plants widely used in Latin America as sedatives and tranquilizers. For this purpose, the infusion of their inflorescences is used to prepare a tea. In this study extracts of inflorescences from Tilia tomentosa Moench, one of the species found in the market, were purified using a benzodiazepine (BZD) binding assay to detect BZD receptor ligands in the different fractions. One of the ligands was identified as kaempferol, but it had low affinity (Ki = 93 microM) for this receptor, and did not produce sedative or anxiolytic effects in mice. On the other hand, a complex fraction, containing as yet unidentified constituents, but probably of a flavonoid nature, when administered intraperitoneally in mice, had a clear anxiolytic effect in both the elevated plus-maze and holeboard tests, two well validated pharmacological tests to measure anxiolytic and sedative compounds. This active fraction had no effect on total and ambulatory locomotor activity. In conclusion, our results demonstrate the occurrence of active principle(s) in, at least, one species of Tilia that may explain its ethnopharmacological use as an anxiolytic.
We report the effects on the central nervous system (CNS) and on analgesic activity of a fraction (F2) obtained from a Himanthalia elongata extract. The fraction was assayed for effects on spontaneous locomotor activity, d-amphetamine-induced hypermotility, motor coordination, muscular relaxation, rectal temperature, sodium pentobarbital-induced hypnosis, and pentylenetetrazole-induced convulsions. Analgesic activity was evaluated using the hot plate test and the Randall-Selitto test (1). The fraction caused significant reductions in spontaneous locomotor activity, hypermotility, rectal temperature, and motor coordination and postponed pentylenetetrazole-induced death, but no effect was noted on muscle relaxation or the duration of sodium pentobarbital-induced sleep. The fraction exhibited central analgesic effects in the hot plate and Randall-Selitto tests.
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