Abstract
Natural products can act as potential GABA modulators, avoiding the undesirable effects of traditional pharmacology used for the inhibition of the central nervous system such as benzodiazepines (BZD). Phenolics, especially flavonoids and phlorotannins, have been considered as modulators of the BZD-site of GABAA receptors (GABAARs), with sedative, anxiolytic or anticonvulsant effects. However, the wide chemical structural variability of flavonoids shows their potential action at more than one additional binding site on GABAARs, which may act either negatively, positively, by neutralizing GABAARs, or directly as allosteric agonists. Therefore, the aim of the present review is to compile and discuss an update of the role of phenolics, namely as pharmacological targets involving dysfunctions of the GABA system, analyzing both their different compounds and their mechanism as GABAergic modulators. We focus this review on articles written in English since the year 2010 until the present. Of course, although more research would be necessary to fully establish the type specificity of phenolics and their pharmacological activity, the evidence supports their potential as GABAAR modulators, thereby favoring their inclusion in the development of new therapeutic targets based on natural products. Specifically, the data compiled in this review allows for the directing of future research towards ortho-dihydroxy diterpene galdosol, the flavonoids isoliquiritigenin (chalcone), rhusflavone and agathisflavone (biflavonoids), as well as the phlorotannins, dieckol and triphlorethol A. Clinically, flavonoids are the most interesting phenolics due to their potential as anticonvulsant and anxiolytic drugs, and phlorotannins are also of interest as sedative agents.
Highlights
The γ-aminobutyric acid (GABA) was discovered in the mammalian brain in 1950 by Jorge Apawara [1], Eugene Roberts and Sam Frankel [2], it was previously synthesized in 1883 when it was only known as a metabolic product in Krebs’ cycle of microorganisms and plants
Flavonoids and GABAA Receptors In the case of flavonoids, despite their well-established role as antioxidants, recent evidence shows their direct interaction with proteins, making them ideal small molecules for the modulation of enzymes, transcription factors, and receptors, and they can act in different ways in several diseases [58]
In the case of the isolated principle dieckol, it increased the GABAA receptors (GABAARs)-mediated inward current in HEK293T cells containing the α1 subunit in a dose-dependent manner, and increased the amplitude of GABAA-BZD receptors in primary cultured neurons. These effects were blocked by co-treatment with flumazenil, thereby corroborating that phlorotannins in general and dieckol in particular act as positive allosteric activators of GABAA-BZD receptors, which justifies the mechanism as sedative-hypnotic [138]. This activity was ratified in vivo by Yoon et al, (2020) which evaluated the effect of dieckol on the sleep-wake state of mice by analysing EEGs and electromyograms, which revealed that it accelerated initiation and increased non-rapid eye movement (NREM) sleep duration and shortened sleep latency
Summary
The γ-aminobutyric acid (GABA) was discovered in the mammalian brain in 1950 by Jorge Apawara [1], Eugene Roberts and Sam Frankel [2], it was previously synthesized in 1883 when it was only known as a metabolic product in Krebs’ cycle of microorganisms and plants. The subunit profile of GABAARs is important for physiological action, and depends on several factors including brain region, cell type, developmental stage, and physiological or pathophysiological conditions [27] They have a different pharmacology and distinctive functional characteristics [28], modulating different functions in the brain. Α5βγ receptors are involved in learning and memory processes [36,37] Some natural products such as terpenoids, polyacetylenic alcohols and certainly flavonoids have demonstrated effects on the GABA system [30], for example, some members of the flavonoid family have shown moderate binding affinities for the BZD-site, thereby positioning themselves as potential targets that could avoid unwanted effects provoked by BZDs. the aim of the present review is to highlight and discuss the role of phenolics as GABA modulators, analyzing the different compounds and their mechanism as GABAergic agents. Despite the large number of publications, only 23 of these 677 articles are clinical trials
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
