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The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects
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| Zeitschriftentitel: | British Journal of Pharmacology |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , |
| In: | British Journal of Pharmacology, 142, 2004, 5, S. 811-820 |
| Format: | E-Article |
| Sprache: | Englisch |
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| author_facet |
Kavvadias, Dominique Sand, Philipp Youdim, Kuresh A Qaiser, M Zeeshan Rice‐Evans, Catherine Baur, Roland Sigel, Erwin Rausch, Wolf‐Dieter Riederer, Peter Schreier, Peter Kavvadias, Dominique Sand, Philipp Youdim, Kuresh A Qaiser, M Zeeshan Rice‐Evans, Catherine Baur, Roland Sigel, Erwin Rausch, Wolf‐Dieter Riederer, Peter Schreier, Peter |
|---|---|
| author |
Kavvadias, Dominique Sand, Philipp Youdim, Kuresh A Qaiser, M Zeeshan Rice‐Evans, Catherine Baur, Roland Sigel, Erwin Rausch, Wolf‐Dieter Riederer, Peter Schreier, Peter |
| spellingShingle |
Kavvadias, Dominique Sand, Philipp Youdim, Kuresh A Qaiser, M Zeeshan Rice‐Evans, Catherine Baur, Roland Sigel, Erwin Rausch, Wolf‐Dieter Riederer, Peter Schreier, Peter British Journal of Pharmacology The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects Pharmacology |
| author_sort |
kavvadias, dominique |
| spelling |
Kavvadias, Dominique Sand, Philipp Youdim, Kuresh A Qaiser, M Zeeshan Rice‐Evans, Catherine Baur, Roland Sigel, Erwin Rausch, Wolf‐Dieter Riederer, Peter Schreier, Peter 0007-1188 1476-5381 Wiley Pharmacology http://dx.doi.org/10.1038/sj.bjp.0705828 <jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>The functional characterization of hispidulin (4′,5,7‐trihydroxy‐6‐methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity.</jats:p></jats:list-item> <jats:list-item><jats:p>After chemical synthesis, hispidulin was investigated at recombinant GABA<jats:sub>A</jats:sub>/BZD receptors expressed by <jats:italic>Xenopus laevis</jats:italic> oocytes. Concentrations of 50 n<jats:sc>M</jats:sc> and higher stimulated the GABA‐induced chloride currents at tested receptor subtypes (<jats:italic>α</jats:italic><jats:sub>1−3,5,6</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S) indicating positive allosteric properties. Maximal stimulation at <jats:italic>α</jats:italic><jats:sub>1</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S was observed with 10 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc> hispidulin. In contrast to diazepam, hispidulin modulated the <jats:italic>α</jats:italic><jats:sub>6</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S‐GABA<jats:sub>A</jats:sub> receptor subtype.</jats:p></jats:list-item> <jats:list-item><jats:p>When fed to seizure‐prone Mongolian gerbils (<jats:italic>Meriones unguiculatus</jats:italic>) in a model of epilepsy, hispidulin (10 mg kg<jats:sup>−1</jats:sup> body weight (BW) per day) and diazepam (2 mg kg<jats:sup>−1</jats:sup> BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group).</jats:p></jats:list-item> <jats:list-item><jats:p>Permeability across the blood–brain barrier for the chemically synthesized, <jats:sup>14</jats:sup>C‐labelled hispidulin was confirmed by a rat <jats:italic>in situ</jats:italic> perfusion model. With an uptake rate (<jats:italic>K</jats:italic><jats:sub>in</jats:sub>) of 1.14 ml min<jats:sup>−1</jats:sup> g<jats:sup>−1</jats:sup>, measurements approached the values obtained with highly penetrating compounds such as diazepam.</jats:p></jats:list-item> <jats:list-item><jats:p>Experiments with Caco‐2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.</jats:p></jats:list-item> </jats:list> </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2004) <jats:bold>142</jats:bold>, 811–820. doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0705828">10.1038/sj.bjp.0705828</jats:ext-link></jats:p> The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects British Journal of Pharmacology |
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kavvadias2004theflavonehispidulinabenzodiazepinereceptorligandwithpositiveallostericpropertiestraversesthebloodbrainbarrierandexhibitsanticonvulsiveeffects |
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2004 |
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| title |
The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_unstemmed |
The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_full |
The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_fullStr |
The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_full_unstemmed |
The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_short |
The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_sort |
the flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| topic |
Pharmacology |
| url |
http://dx.doi.org/10.1038/sj.bjp.0705828 |
| publishDate |
2004 |
| physical |
811-820 |
| description |
<jats:p>
<jats:list list-type="explicit-label">
<jats:list-item><jats:p>The functional characterization of hispidulin (4′,5,7‐trihydroxy‐6‐methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity.</jats:p></jats:list-item>
<jats:list-item><jats:p>After chemical synthesis, hispidulin was investigated at recombinant GABA<jats:sub>A</jats:sub>/BZD receptors expressed by <jats:italic>Xenopus laevis</jats:italic> oocytes. Concentrations of 50 n<jats:sc>M</jats:sc> and higher stimulated the GABA‐induced chloride currents at tested receptor subtypes (<jats:italic>α</jats:italic><jats:sub>1−3,5,6</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S) indicating positive allosteric properties. Maximal stimulation at <jats:italic>α</jats:italic><jats:sub>1</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S was observed with 10 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc> hispidulin. In contrast to diazepam, hispidulin modulated the <jats:italic>α</jats:italic><jats:sub>6</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S‐GABA<jats:sub>A</jats:sub> receptor subtype.</jats:p></jats:list-item>
<jats:list-item><jats:p>When fed to seizure‐prone Mongolian gerbils (<jats:italic>Meriones unguiculatus</jats:italic>) in a model of epilepsy, hispidulin (10 mg kg<jats:sup>−1</jats:sup> body weight (BW) per day) and diazepam (2 mg kg<jats:sup>−1</jats:sup> BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group).</jats:p></jats:list-item>
<jats:list-item><jats:p>Permeability across the blood–brain barrier for the chemically synthesized, <jats:sup>14</jats:sup>C‐labelled hispidulin was confirmed by a rat <jats:italic>in situ</jats:italic> perfusion model. With an uptake rate (<jats:italic>K</jats:italic><jats:sub>in</jats:sub>) of 1.14 ml min<jats:sup>−1</jats:sup> g<jats:sup>−1</jats:sup>, measurements approached the values obtained with highly penetrating compounds such as diazepam.</jats:p></jats:list-item>
<jats:list-item><jats:p>Experiments with Caco‐2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.</jats:p></jats:list-item>
</jats:list>
</jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2004) <jats:bold>142</jats:bold>, 811–820. doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0705828">10.1038/sj.bjp.0705828</jats:ext-link></jats:p> |
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| author | Kavvadias, Dominique, Sand, Philipp, Youdim, Kuresh A, Qaiser, M Zeeshan, Rice‐Evans, Catherine, Baur, Roland, Sigel, Erwin, Rausch, Wolf‐Dieter, Riederer, Peter, Schreier, Peter |
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| description | <jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>The functional characterization of hispidulin (4′,5,7‐trihydroxy‐6‐methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity.</jats:p></jats:list-item> <jats:list-item><jats:p>After chemical synthesis, hispidulin was investigated at recombinant GABA<jats:sub>A</jats:sub>/BZD receptors expressed by <jats:italic>Xenopus laevis</jats:italic> oocytes. Concentrations of 50 n<jats:sc>M</jats:sc> and higher stimulated the GABA‐induced chloride currents at tested receptor subtypes (<jats:italic>α</jats:italic><jats:sub>1−3,5,6</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S) indicating positive allosteric properties. Maximal stimulation at <jats:italic>α</jats:italic><jats:sub>1</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S was observed with 10 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc> hispidulin. In contrast to diazepam, hispidulin modulated the <jats:italic>α</jats:italic><jats:sub>6</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S‐GABA<jats:sub>A</jats:sub> receptor subtype.</jats:p></jats:list-item> <jats:list-item><jats:p>When fed to seizure‐prone Mongolian gerbils (<jats:italic>Meriones unguiculatus</jats:italic>) in a model of epilepsy, hispidulin (10 mg kg<jats:sup>−1</jats:sup> body weight (BW) per day) and diazepam (2 mg kg<jats:sup>−1</jats:sup> BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group).</jats:p></jats:list-item> <jats:list-item><jats:p>Permeability across the blood–brain barrier for the chemically synthesized, <jats:sup>14</jats:sup>C‐labelled hispidulin was confirmed by a rat <jats:italic>in situ</jats:italic> perfusion model. With an uptake rate (<jats:italic>K</jats:italic><jats:sub>in</jats:sub>) of 1.14 ml min<jats:sup>−1</jats:sup> g<jats:sup>−1</jats:sup>, measurements approached the values obtained with highly penetrating compounds such as diazepam.</jats:p></jats:list-item> <jats:list-item><jats:p>Experiments with Caco‐2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.</jats:p></jats:list-item> </jats:list> </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2004) <jats:bold>142</jats:bold>, 811–820. doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0705828">10.1038/sj.bjp.0705828</jats:ext-link></jats:p> |
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| match_str | kavvadias2004theflavonehispidulinabenzodiazepinereceptorligandwithpositiveallostericpropertiestraversesthebloodbrainbarrierandexhibitsanticonvulsiveeffects |
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| spelling | Kavvadias, Dominique Sand, Philipp Youdim, Kuresh A Qaiser, M Zeeshan Rice‐Evans, Catherine Baur, Roland Sigel, Erwin Rausch, Wolf‐Dieter Riederer, Peter Schreier, Peter 0007-1188 1476-5381 Wiley Pharmacology http://dx.doi.org/10.1038/sj.bjp.0705828 <jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>The functional characterization of hispidulin (4′,5,7‐trihydroxy‐6‐methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity.</jats:p></jats:list-item> <jats:list-item><jats:p>After chemical synthesis, hispidulin was investigated at recombinant GABA<jats:sub>A</jats:sub>/BZD receptors expressed by <jats:italic>Xenopus laevis</jats:italic> oocytes. Concentrations of 50 n<jats:sc>M</jats:sc> and higher stimulated the GABA‐induced chloride currents at tested receptor subtypes (<jats:italic>α</jats:italic><jats:sub>1−3,5,6</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S) indicating positive allosteric properties. Maximal stimulation at <jats:italic>α</jats:italic><jats:sub>1</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S was observed with 10 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc> hispidulin. In contrast to diazepam, hispidulin modulated the <jats:italic>α</jats:italic><jats:sub>6</jats:sub><jats:italic>β</jats:italic><jats:sub>2</jats:sub><jats:italic>γ</jats:italic><jats:sub>2</jats:sub>S‐GABA<jats:sub>A</jats:sub> receptor subtype.</jats:p></jats:list-item> <jats:list-item><jats:p>When fed to seizure‐prone Mongolian gerbils (<jats:italic>Meriones unguiculatus</jats:italic>) in a model of epilepsy, hispidulin (10 mg kg<jats:sup>−1</jats:sup> body weight (BW) per day) and diazepam (2 mg kg<jats:sup>−1</jats:sup> BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group).</jats:p></jats:list-item> <jats:list-item><jats:p>Permeability across the blood–brain barrier for the chemically synthesized, <jats:sup>14</jats:sup>C‐labelled hispidulin was confirmed by a rat <jats:italic>in situ</jats:italic> perfusion model. With an uptake rate (<jats:italic>K</jats:italic><jats:sub>in</jats:sub>) of 1.14 ml min<jats:sup>−1</jats:sup> g<jats:sup>−1</jats:sup>, measurements approached the values obtained with highly penetrating compounds such as diazepam.</jats:p></jats:list-item> <jats:list-item><jats:p>Experiments with Caco‐2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.</jats:p></jats:list-item> </jats:list> </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2004) <jats:bold>142</jats:bold>, 811–820. doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0705828">10.1038/sj.bjp.0705828</jats:ext-link></jats:p> The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects British Journal of Pharmacology |
| spellingShingle | Kavvadias, Dominique, Sand, Philipp, Youdim, Kuresh A, Qaiser, M Zeeshan, Rice‐Evans, Catherine, Baur, Roland, Sigel, Erwin, Rausch, Wolf‐Dieter, Riederer, Peter, Schreier, Peter, British Journal of Pharmacology, The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects, Pharmacology |
| title | The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_full | The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_fullStr | The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_full_unstemmed | The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_short | The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_sort | the flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| title_unstemmed | The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects |
| topic | Pharmacology |
| url | http://dx.doi.org/10.1038/sj.bjp.0705828 |