Synergistic interaction between hesperidin, a natural flavonoid, and diazepam.
It has been recently reported the presence in Valeriana of the flavone 6-methylapigenin and the flavanone glycoside hesperidin. The apigenin derivative is a ligand for the benzodiazepine binding site in the gamma-aminobutyric acid receptor type A (GABA(A)) and has anxiolytic properties. Hesperidin has sedative and sleep-enhancing properties but is not a ligand for the benzodiazepine binding site. 6-Methylapigenin is able to potentiate the sleep-enhancing effect of hesperidin. In this work we demonstrate that this property is shared with various GABA(A) receptor ligands, among them the agonist diazepam, which was used to study the potentiation as measured in the hole board test. Isobolar analysis of the results showed the interaction being synergistic. We discarded pharmacokinetic effects or a direct action of hesperidin on the benzodiazepine binding site. A possible use of hesperidin properties to decrease the effective therapeutic doses of benzodiazepines is suggested.
Fernández
Sebastián P
SP
Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Junín 956 (C1113AAD), Buenos Aires, Argentina.
Wasowski
Cristina
C
Paladini
Alejandro C
AC
Marder
Mariel
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D003975:Diazepam / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D006569:Hesperidin / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D012890:Sleep / Q000187:drug effects; D014316:Tritium
C469106:6-methylapigenin; D005419:Flavonoids; D006993:Hypnotics and Sedatives; D008024:Ligands; D014316:Tritium; D001569:Benzodiazepines; D005445:Flunitrazepam; D006569:Hesperidin; D003975:Diazepam