Characterization of 6-methoxyflavanone as a novel anxiolytic agent: A behavioral and pharmacokinetic approach

• Published in: European journal of pharmacology 2017-04, Vol.801, p.19-27
• Main Authors: Akbar, Shehla, Subhan, Fazal, Karim, Nasiara, Aman, Urooj, Ullah, Sami, Shahid, Muhammad, Ahmad, Nisar, Fawad, Khwaja, Sewell, Robert D.E.
• Format: Article
• Language: English
• Subjects: 6-Methoxyflavanone; 6-Methoxyflavanone (PubChem CID: 97860); Allosteric Regulation - drug effects; Amygdala - drug effects; Amygdala - metabolism; Amygdala - physiology; Animals; Anti-Anxiety Agents - pharmacokinetics; Anti-Anxiety Agents - pharmacology; anxiety; Behavior, Animal - drug effects; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - physiology; elevated plus-maze; Female; Flavanones - pharmacokinetics; Flavanones - pharmacology; Flavonoid; GABAA receptors; Male; Maze Learning - drug effects; Mice; Motor Activity - drug effects; Receptors, GABA-A - metabolism; staircase anxiety test
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.02.047

Benzodiazepines are regularly prescribed for treatment of anxiety though there are side effects. Flavonoids have selective affinity for GABAA receptors 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 GABAA receptors, 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.