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

被引:18
作者
Akbar, Shehla [1 ]
Subhan, Fazal [1 ]
Karim, Nasiara [2 ]
Aman, Urooj [1 ]
Ullah, Sami [1 ]
Shahid, Muhammad [1 ]
Ahmad, Nisar [1 ]
Fawad, Khwaja [1 ]
Sewell, Robert D. E. [3 ]
机构
[1] Univ Peshawar, Dept Pharm, Peshawar, Khyber Pakhtunk, Pakistan
[2] Univ Malakand, Dept Pharm, Chakdara, Pakistan
[3] Cardiff Univ, Cardiff Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales
关键词
Flavonoid; 6-Methoxyflavanone; anxiety; GABA(A) receptors; elevated plus-maze; staircase anxiety test; ELEVATED PLUS-MAZE; STAIRCASE TEST; BENZODIAZEPINE-RECEPTORS; GABA(A) RECEPTORS; OPEN-FIELD; ANXIETY; MICE; AMYGDALA; MOUSE; FLAVONOIDS;
D O I
10.1016/j.ejphar.2017.02.047
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 gamma-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 50 mg/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 (100 mg/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 (15 mg/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.
引用
收藏
页码:19 / 27
页数:9
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