Table 2.
Flavones with relevant GABAergic effects. Aβ (β-amyloid), APP (amyloid precursor protein), EPM (elevated plus-maze), HSP70 (heat shock protein-70), MAPK (mitogen-activated protein kinase), REM (rapid eye movement), SW (slow wave).
 Flavone | ||
|---|---|---|
| Compound | Properties | Reference |
| Apigenin (5,7,4’-trihydroxy) | Apigenin enhances pentobarbital-induced sleep behaviours through chloride ion channel activation. | [77] |
| Apigenin reduces the frequency of spontaneous excitatory postsynaptic currents without affecting their amplitude, suggesting a presynaptic mechanism. | [78] | |
| Luteolin (5,7,3’,4’-trihydroxy) | Luteolin ameliorates mechanical and cold hyperalgesia at least in part by activation of GABAARs in a flumazenil-insensitive manner and μ-opioid receptors in the spinal cord. | [79] |
| Luteolin attenuates mucus overproduction and goblet cell hyperplasia in an animal asthma model at least partially by inhibition of GABAAR activities. | [80] | |
| Luteolin has negative modulatory effects on both recombinant and endogenous GABAARs and inhibits phasic rather than tonic inhibition in the hippocampus. | [81] | |
| The antidepressant-like effect of Cirsium japonicum could be mediated by luteolin through the potentiation of the GABAA receptor-Cl− ion channel complex. | [82] | |
| Chrysin (5,7-dihydroxy) | Chrysin prevents anxiety-like behaviour during metestrus-diestrus in two unconditioned models. These effects were mediated by actions on GABAARs. | [83] |
| Chrysin produces anxiolytic-like effects through actions on GABAARs in a model of surgical menopause in rats. | [84] | |
| Chrysin has more than one mechanism of action in addition to its action at the GABAA-BZD receptor complex, and also could be involved in its free radical scavenging abilities. | [85] | |
| The acute antidepressant-like effects of chrysin, similar to neurosteroids, are mediated by the GABA-binding site at GABAARs in ovariectomized rats. | [86] | |
| Baicalein (5,6,7-trihydroxy) | The anticonvulsive effect of baicalein was mediated by the BZD binding site of GABAAR. The 5,7-dihydroxyl group is present in the structure of the three flavones, playing a key role in inducing convulsion-related activities. | [87] |
| Baicalein promotes non-amyloidogenic processing of APP, thereby reducing Aβ production and improving cognitive performance by activation of GABAARs. | [88] | |
| It exhibits biphasic effects on sleep–wake regulation; decreases the SW sleep during the light period and increases SW sleep and REM sleep during the dark period. | [89] | |
| Wogonin (5,7-dihydroxy-8-methoxy) | Wogonin is a 2.8-fold stronger ligand to the BZD binding site (Ki = 2.03 μM) compared to baicalein (Ki = 5.69 μM). | [90] |
| Oroxylin A (5,7-dihydroxy-6-methoxy) | In vitro studies reveal that oroxylin A blocked muscimol-induced intracellular Cl− influx. | [87] |
| Oroxylin A has the highest brain uptake and the highest affinity to brain tissues (In vitro tissue binding assay) compared to other flavones. This flavone, a GABAA antagonist, can suppress the anxiolytic effects of other flavones present in the extract. | [91] | |
| Glabrol (7,4’-dihydroxy-8,3’-di-isoprenyl) | Glabrol inhibits [3H]-flumazenil binding site to the GABAA-BZD receptors in the rat cerebral cortex membrane with a binding affinity (Ki) of 1.63 μM. The isoprenyl groups may play a key role in binding to GABAA-BZD receptors. Glabrol increases sleep duration and decreases sleep latency via a positive allosteric modulation of GABAA-BZD receptors. | [92] |
| 5-Methoxyflavone | In silico studies indicate that 5-methoxyflavone exhibits good binding affinity towards GABAA, adenosine, glycine and NMDA receptors by H-bond interactions, justifying its hypnotic effect. | [93] |
| In silico studies demonstrate a good binding affinity of 5-methoxyflavone towards GABAA (α2 subunit-containing) and serotoninergic 5-HT1A receptors by H-bond interactions. | [94] | |
| 7,8-Dihydroxyflavone | 7,8-Dihydroxyflavone causes a selective reduction in the strength of GABAergic inhibition after incubation with acute cortical slices. | [95] |
| 3-Hydroxy-2’methoxy-6-methylflavone | 3-Hydroxy-2’methoxy-6-methylflavone has an anxiolytic effect without sedation or myorelaxation through positive allosteric modulation of the α2β2/3γδ2L and direct activation of α4β2/3δ GABAAR subtypes. | [96] |
| 2’-Methoxy-6-methylflavone | 2’-Methoxy-6-methylflavone could be used as a tool to study the complex nature of the activation and modulation of GABAAR subtypes. | [97] |
| 3,5,6,7,8,3’-hexamethoxy-4’,5’-methylenedioxyflavone | This methylenedioxyflavone shows anxiolytic-like activity in the EPM but locomotor responses remain unchanged. | [98] |
| 6,7,4’,5’-dimethylenedioxy-3,5,3’-trimethoxyflavone | This methoxyflavone has anxiolytic-like activity in the EPM test involving GABAAR reversed by flumazenil. | [98] |
| 3,3’,4’,5,5’,8-hexamethoxy-6,7-methylenedioxyflavone | This methylenedioxyflavone shows anxiolytic-like activity in the EPM test, with the implication of GABAAR, but locomotor responses remain unchanged. | [98] |
| 6-Methoxyflavone/8-Methoxyflavone 5,7,2’,4’-Tetrahydroxy-6,5’-dimethoxyflavone |
The structure-activity relationships analysis of 28 flavonoids indicate that 6-and/or 8-methoxy flavones had the most potent binding affinity to GABAARs. Of them, compound 5,7,2’,4’-tetrahydroxy-6,5’-dimethoxyflavone (IC50 0.10 μM) had the higher anticonvulsant activity against chemically-induced and electrogenic seizures without myorelaxation and sedation. | [99] |
| Glycosides | ||
| Scutellarin (scutellarein-7-O-glucuronide) | Scutellarin is identified by integrated metabolomics and proteomics approach as the active ingredient of Dengzhan Shengmai acting against chronic cerebral hypoperfusion due to the regulation of glutamatergic and GABAergic synapses. | [100] |
| Baicalin (baicalein 7-O-glucuronide) | Baicalin does not change intracellular Cl− concentration, whereas its aglycone does. Glycosylation has a negative influence on the affinity for the BZD-binding site of the GABAAR. | [87] |
| Baicalin activates GABAergic signalling, HSP70 and MAPKs cascades in global ischemia, which may be a mechanism underlying the baicalin’s neuroprotection. | [101] | |
| Baicalin inhibits SG neurons activating the BZD-sensitive GABAAR and/or glycine receptors, becoming a potential target for orofacial pain modulation. | [102] | |
| Vitexin (apigenin 8-C-glucoside) | Vitexin has anticonvulsant effects possibly through interaction at the BZD-binding site of the GABAAR complex. | [103] |
| Isovitexin (apigenin 6-C-glucoside) | Isovitexin could exert its memory-enhancing and anxiolytic-like effects via GABAA R modulation through its BZD-binding site. | [104] |
| Spinosin (apigenin 7-O-methyl-6-O-diglucoside) | Spinosin exerts anxiolytic-like effects with a mechanism of action modulated by GABAA and serotoninergic 5-HT1A receptors. | [105] |