**4.1 Flavonoid-receptor interactions**

There are a number of studies that support the flavonoid-receptor interactions. For example, blueberry intake by young rodents increases the levels of GluN2b subunit of N-methy-d-aspartate receptor (NMDAR) in hippocampus [30]. Similarly, in young rodents, acute effect of oral flavonoid-rich fraction (Ff) intake up-regulated mRNA expression of the GluN2b subunit in dorsal hippocampus [5]. The flavonoid-rich fraction (Ff) containing flavones (Vitexin, Isovitexin, and 6-C-glycoside-Diosmetin) and improves learning and memory in young rodents. It is known that NMDARs are centrally involved in synaptic transmission, synaptic plasticity (long-term potentiation – LTP and long-term depression – LTD), and learning and memory [31]. According to this, quercetin resulted in improvements of hippocampal CA1 long-term potentiation in acute hippocampal slice from young rats [32].

The serotoninergic and GABAergic neurotransmissions are involved in learning and memory; the major targets are 5-HT1ARs and GABAARs, and the modulation of these receptors in the hippocampus is essential for the acquisition and consolidation of memory [33–35]. Supporting, acute effect of oral Ff up-regulated mRNA expression of the 5-HT1AR and GABA(A) alpha 5 receptor in dorsal hippocampus from young rats [5]. Molecular docking study showed that flavones such as Isovitexin and 6-C-glycoside-Diosmetin exhibited a strong interaction with the GABAA BZ binding pocket. Those flavones showed a lack of interaction with α1His101, which may explain the memory-enhancing effect identified in the behavioral test in young rats [36].

Flavonoids can modulate other receptors such as TrKB [37], δ-opioid [38, 39], nicotinic [40, 41], estrogen [42, 43], and adenosine [44–46]. For example, 7,8-dihydroxyflavone, a flavone, was shown high-affinity agonist of the TrKB receptor [47]. In addition, the flavones may improve cognition by modulating the acetylcholine and neurotrophic factors synthesis in hippocampus and frontal cortex [27, 48]. Those flavonoid-binding sites show many possibilities of flavonoids action mechanisms to modulate cognition and brain physiology.
