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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 |
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| Personen und Körperschaften: | , , , , , , , , , |
| In: | British Journal of Pharmacology, 142, 2004, 5, S. 811-820 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| Zusammenfassung: | <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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| Umfang: | 811-820 |
| ISSN: |
0007-1188
1476-5381 |
| DOI: | 10.1038/sj.bjp.0705828 |