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Isolation and characterization of benzodiazepine receptor ligand from Scutellaria baicalensis Georgi

Authors Hui, Kwok-Min
Issue Date 2000
Summary Several naturally occuring monoflavonoids, isolated from Scutellaria baicalensis Georgi using silica gel and LH-20 chromatography, inhibited [3H] flunitrazepam binding to the central benzodiazepine receptors (BDZ-Rs) with high to moderately low binding affinity. The most potent one is 5,7,2’-trihydroxy-6,8-dimethoxyflavone (K36) with a Ki of 7.7 nM and the weakest one is baicalin with a Ki of 77.1 μM. The functional properties of wogonin (Ki=1.06 μM) and K36 were determined by electrophysiological studies, employing dorsal root ganglion (DRG) neurons and recombinant GABAA receptor functionally expressed in Xenopus laevis oocytes. Wogonin and K36 brought about an enhancement of the GABA-activated current, which could be reversed by the co-application of BDZ-R antagonist Ro15-1788. Threshold of stimulation is 0.3-1 μM for wogonin and 1-3 nM for K36. Both wogonin and K36 act as partial positive allosteric modulator at the preference BDZ-R. The pharmacological effects of wogonin and dichloromethane (DCM) extract were examined in mice. For the large-scale preparation of wogonin, it was crystallized directly from the DCM extract instead of using silica gel chromatography. The purity of the crystal (wogonin) was up to 95 %, which was determined by TLC and HPLC. The acute toxicity of wogonin and DCM extract was low with a LD50 of 3.9 g/kg and 5.9 g/kg, respectively. In acute treatment, wogonin (7.5-30 mg/kg), DCM extract (4-16 mg/kg) and diazepam (1 mg/kg) had a significant anxiolytic effect in the elevated plus-maze test for anxiety. In chronic treatment (5 days pre-treatment), the anxiolytic effect of wogonin (15-30 mg/kg), DCM extract (8 mg/kg) and diazepam (1 mg/kg) were significantly reduced. The anxiolytic effect of wogonin (15 mg/kg ) and DCM extract (8 mg/kg ) was abolished by the BDZ-R antagonist Ro15-1788 (1.25 mg/kg). Wogonin (3.75-30 mg/kg), DCM extract (4-16 mg/kg) and diazepam (1 mg/kg) did not exert any significant effect on locomotor activity acutely or chronically. In the hole-board test, wogonin (7.5-30 mg/kg) and diazepam (1 mg/kg) increased the number of head dips and the time spent in head-dipping both acutely and chronically. However, they had no significant effect on the number of rearing. DCM extract (4-16 mg/kg) had no significant effect on the number of head dips, time spent in head-dipping and rearing acutely and chronically. Based on the results of hole-board test, both wogonin and DCM extract did not have the sedative effect. In the horizontal wire test, diazepam (6 mg/kg) but not wogonin (3.75-30 mg/kg) and DCM extract (4-16 mg/kg) displayed myorelaxant actions. The results showed that wogonin and K36 are naturally occurring partial positive allosteric modulator of the GABAA receptor acting at the BDZ-R. Wogonin could be crystallized directly from the DCM extract instead of purifying by silica gel chromatography. Wogoin and DCM extract have a low acute lethality and exert an anxiolytic action without evident myorelaxant and sedative effects. The dose of 7.5 mg/kg (wogonin) and 4 mg/kg (DCM extract) can be used in chronic treatment.
Note Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2000
Language English
Format Thesis
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