title: GABA(A) receptor modulation and neuropharmacological activities of viscosine isolated from Dodonaea viscosa (Linn).
abstract: The objective of the present study was to evaluate the modulation of GABA-evoked currents by the flavonoid viscosine at recombinant GABA(A) receptors, and subsequently to study its anxiolytic, sedative and anticonvulsant activities. Viscosine (1-300μM) positively modulated GABA-evoked currents at human α1β2γ2L and α2β2γ2L GABA(A) receptors expressed in Xenopus oocytes in a flumazenil insensitive manner. In behavioral studies, viscosine at doses of 10-100mg/kg (i.p.) exerted significant anxiolytic effects in the elevated plus maze, light-dark and open field tests (*P<0.05, **P<0.01, ***P<0.001 n=6, One-way ANOVA post-Dunnett's test), and sedative effects at high doses (100mg/kg i.p.) in hole board and thiopental induced sleep time tests. The anxiolytic effect in the elevated plus maze test was not blocked by flumazenil whereas pentylenetetrazole (PTZ) completely attenuated the effect, indicating that the activity was mediated via the non-benzodiazepine sites of GABA(A) receptors. Furthermore, viscosine at doses of 10-100mg/kg (i.p.) exerted anticonvulsant effects in a dose-dependent manner in PTZ, picrotoxin and bicuculline induced seizure paradigms (*P<0.05, **P<0.01,***P<0.001 n=6, One-way ANOVA post-Dunnett's test). In conclusion, the results of the present study suggest that the anxiolytic and anticonvulsant actions of viscosine are likely mediated via its positive allosteric modulatory action of GABA at different GABA(A) receptor subtypes.
authors.affiliation: Department of Pharmacy, University of Malakand, Chakdara, Pakistan; Faculty of Pharmacy, The University of Sydney, NSW, Australia. Electronic address: nasiara.karim@hotmail.com.
authors.forename: Nasiara
authors.initials: N
authors.lastname: Karim
authors.affiliation: Department of Pharmacy, University of Malakand, Chakdara, Pakistan.
authors.forename: Shahid
authors.initials: S
authors.lastname: Irshad
authors.affiliation: Department of Pharmacy, University of Malakand, Chakdara, Pakistan.
authors.forename: Imran
authors.initials: I
authors.lastname: Khan
authors.affiliation: Department of Chemistry, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Akhtar
authors.initials: A
authors.lastname: Mohammad
authors.affiliation: Department of Chemistry, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Itrat
authors.initials: I
authors.lastname: Anis
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Muhammad Raza
authors.initials: MR
authors.lastname: Shah
authors.affiliation: Department of Pharmacy, University Peshawar, Peshawar, Pakistan.
authors.forename: Inamullah
authors.initials: I
authors.lastname: Khan
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007529:Isoflavones / Q000302:isolation & purification / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000502:physiology*; D029631:Sapindaceae / Q000737:chemistry*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D007529:Isoflavones; D011963:Receptors, GABA-A; C000607529:viscosine; D005680:gamma-Aminobutyric Acid
keywords: Anticonvulsant; Anxiolytic; Flavonoids; GABA; Viscosine; Xenopus oocytes