**4.2 Flavonoid-signaling pathways interactions**

Receptor binding by flavonoids is responsible by changes in the up-regulated and down-regulated pathways such as, PI3K, PKC, MAP kinases, and nuclear factor-κB pathway. Their influence on such pathways suggests that they may modulate synaptic plasticity involved in neurodegenerative diseases, and memory acquisition, consolidation, and storage.

Short-term and long-term treatment of oral *Ginkgo biloba* (EGb) extract upregulated mRNA and protein of the CREB-1 and GAP-43 in dorsal hippocampus

**Figure 2.** *Mechanisms underpinning the actions of flavonoids.*

from young rats [49, 50]. These molecules are associated with molecular mechanism LTP, and it has been shown that the transcription factor, cAMP response elementbinding protein (CREB), may regulate the synthesis of new proteins necessary for the formation of memory. Another potential protein associated with LTP is the protein 43-kDa growth-associated protein (GAP-43), and they dramatically enhances during LTP [51–53]. Quercetin-increased expression of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) [54] pathway is important for memory.

Flavanols and flavanones activate the ERK pathway [55–58] and ERK modulate cAMP response element binding protein (CREB) activation, which is involved in long-term changes in synapses and memory formation [37–39]. Similarly, acute effect of oral Ff up-regulated mRNA expression of the ERK in dorsal hippocampus from young rats [5].

In addition, the flavonoids may modulate the protein kinases, as MAP-kinase and PI3-kinase [59–62], the alteration on activation of kinase may influence directly on modulation of activity-dependent plasticity and morphological changes in synapses involved in memory acquisition, consolidation, and storage [63].

In summary, the ability of flavonoids to influence receptor activity and synaptic plasticity suggest that these might underpin enhancements in cognitive functions in both health conditions and neurological/psychiatric disorders. Additional approaches are required to understand the molecular mechanisms involved in these processes, for example, electrophysiological studies in rodents and human.
