title: Characterization of 6-methoxyflavanone as a novel anxiolytic agent: A behavioral and pharmacokinetic approach.
abstract: Benzodiazepines are regularly prescribed for treatment of anxiety though there are side effects. Flavonoids have selective affinity for GABAAreceptors implicated in anxiolytic-like activity in rodents, but are devoid of the unwanted side effects of benzodiazepines. In this study, 6-methoxyflavanone (6-MeOF), a positive allosteric modulator of γ-amino butyric acid (GABA) responses at human recombinant GABAAreceptors, was evaluated for its behavioral profile in the elevated plus-maze as well as the staircase- plus and open-field tests in mice. In addition, the distribution of 6-MeOF in selected brain areas involved in anxiety (amygdala and cerebral cortex) was also examined using a validated high performance liquid chromatography ultraviolet detection (HPLC/UV) method. 6-MeOF (10, 30 and 50mg/kg) exerted an anxiolytic-like effect, increasing entries and time spent in the open arm and the central platform, as well as head-dipping frequency in the mouse elevated plus-maze assay. It also decreased rearing incidence without suppressing the number of steps ascended in the staircase test. Whereas, in the open-field anxiety test, 6-MeOF had no effect on locomotor activity at lower doses, a decrease was observed at the highest dose (100mg/kg). 6-MeOF additionally produced an anxiolytic-like increase in the time spent at the center of the open-field apparatus. These effects were preferentially antagonized by pentylenetetrazole (15mg/kg). Furthermore, pharmacokinetic studies disclosed a rapid appearance of 6-MeOF in the plasma and discrete brain areas. Taken together, our findings suggest that 6-MeOF readily crosses the blood brain barrier (BBB) generating anxiolytic activity, mediated through the GABAergic system.
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: naina.akbar@yahoo.com.
authors.forename: Shehla
authors.initials: S
authors.lastname: Akbar
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: fazal_subhan@upesh.edu.pk.
authors.forename: Fazal
authors.initials: F
authors.lastname: Subhan
authors.affiliation: Department of Pharmacy, University of Malakand, Chakdara, Pakistan. Electronic address: nasiara.karim@hotmail.com.
authors.forename: Nasiara
authors.initials: N
authors.lastname: Karim
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: ua_pharm@yahoo.com.
authors.forename: Urooj
authors.initials: U
authors.lastname: Aman
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: samiullah@upesh.edu.pk.
authors.forename: Sami
authors.initials: S
authors.lastname: Ullah
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: shahidsalim_2002@hotmail.com.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Shahid
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: nisarahmadsatal@yahoo.com.
authors.forename: Nisar
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: fawad.khwaja@yahoo.com.
authors.forename: Khwaja
authors.initials: K
authors.lastname: Fawad
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK. Electronic address: sewell@cardiff.ac.uk.
authors.forename: Robert D E
authors.initials: RD
authors.lastname: Sewell
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005260:Female; D044950:Flavanones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: C000598908:6-methoxyflavanone; D014151:Anti-Anxiety Agents; D044950:Flavanones; D011963:Receptors, GABA-A
keywords: 6-Methoxyflavanone; 6-Methoxyflavanone (PubChem CID: 97860); Flavonoid; GABA(A) receptors; anxiety; elevated plus-maze; staircase anxiety test