# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 2 Activities of Flavonoids from Natural Sources
### Inhibition of Pro-Inflammatory Factors
#### 2.3.3 Flavones  
Several flavones have an inhibitory effect on the pro-inflammatory factors. Apigenin (**29**) decreases the production of pro-inflammatory IL-6 and TNF-\(\alpha\) through mechanisms involving STAT1. Further evidence of the anti-inflammatory activity of this flavonoid was provided in investigations showing reduction in iNOS/NO and PGE2/COX-2 in activated microglia [47]. Luteolin (**34**) attenuates IL-6, TNF-\(\alpha\), COX-2 and iNOS gene expression in activated microglia, and inhibits cytokine-induced neuronal death [47; 54; 75]. This flavone inhibits the NO level with an IC\({}_{50}\) value of 1.74 uM [76].  
Studies in vitro revealed that diosmtein (**33**) decreases the production of pro-inflammatory mediators [47] and that scutellarin (**91**) also decreases the production of pro-inflammatory mediators as the expression of NF-kB [47]. Wogonin (**92**) suppresses the activity of NF-\(\kappa\)B and the iNOS expression [75; 94]. Baicalein (**30**) decreases the inflammatory processes and neuronal death by the inhibition of iNOS/NO [54]. These two flavones (**92** and **30**) inhibit the NO level with IC\({}_{50}\) values of 45.3 and 66.4 uM, respectively [71].  
Considering the isoflavones genistein (**2**, Figure 3), or daidzein (**3**, Figure 3), they possess anti-inflammatory effects against activated microglial cell line inhibiting iNOS and IL-6 expression [47]. Nine isoflavones, isolated from _Iris pseudopmila_ Tineo, inhibit the NO level with IC\({}_{50}\) values ranging from 23.60 to 98.30 uM, such as: irilione, the 4',5-dihydroxy-6,7-methylenedioxyisoflavone (**93**, 89.70 uM); 4'-O-(\(\beta\)-d-glucopyranosyl)-5-hydroxy-6,7-methylenedioxyisoflavone (**94**, 80.10 uM); 4'-O-[\(\beta\)-d-glucopyranosyl-(1\(\rightarrow\)6)-\(\beta\)-d-glucopyranosyl)-6,7-methylenedioxyisoflavone (**95**, 83.60 uM); 4'-O-(\(\beta\)-d-glucopyranosyl)-7-O-methylenedioxyisoflavone (**95**, 83.60 uM); 4'-O-(\(\beta\)-d-glucopyranosyl)-7-O-methylenedioxyisoflavone (**96**, 56.90 uM); 4'-O-[\(\beta\)-d-glucopyranosyl)-1-6,7-methylenedioxyisoflavone (**97**, 85.90 uM); 4'-O-(\(\beta\)-d-glucopyranosyl)-5-hydroxy-6,7-dimethylenedioxin (**96**, 56.90 uM); 4'-O-[\(\beta\)-d-glucopyranosyl)-1-6,7-methylenedioxyisoflavone (**101**, 23.60 uM). Thus, comparing the IC\({}_{50}\) values for 96 (IC\({}_{50}\) = 56.90 uM) and **97** (IC\({}_{50}\) = 29.40 uM), it is concluded that the presence of disaccharidely moiety increases the activity against the NO production. The same occurred relatively to **99** (IC\({}_{50}\) = 98.30 uM) and **100** (IC\({}_{50}\) = 55.10 uM) [81].  
Glycosalated flavones such as isoorientin (**47**), isovievein (**44**), and 6\"-O-(\(\beta\)-d-glucopyranosyl) isoorientin (**102**), isolated from _Iris pseudopmila_ Tineo, exhibit inhibitory activity against NO production with IC\({}_{50}\) values of 61.00, 66.70 and 71.90 uM, respectively [81].  
Considering biflavonoids such as ginkgetin (**63**), bilobetin (**60**), taivaniaflavone (**103**) and amentoflavone (**58**) they downregulate the expression of COX-2 and iNOS [85].