## 5 Therapeutic Implications of WA in AD
### Role of WA and Its Derivatives
#### 5.1.4 WA Blocks the Neuroinflammation in AD  
WA Inhibits the NF-kB Pathway  
In normal and pathophysiological immune responses, the transcription factor NF-kB and its activation signaling pathways play a critical role, making it an interesting therapeutic target. Therefore, WZA has been extensively studied to investigate its effect on the signaling NF-kB activation [163; 164; 165]. WA decreases inflammatory mediators including TNF-\(\alpha\) and IL-1 in plaque formation and neurodegeneration [152; 166; 167; 156]. _W. somifera_ is anti-inflammatory due to the presence of WA. Research findings indicated that WA effectively prevents the activation of NF-kB by stopping phosphorylation and deterioration by inhibiting stimulation of 1 kB kinase, while other _W. somifera_ derived steroidal lactones, like withanolide A, are far less effective [168]. Moreover, WA inhibits NF-kB activation by attacking cysteine 179 located at the IKK\(\beta\) catalytic site [165]. Furthermore, nitric oxide and COX-2 production are inhibited by WA by inhibiting nitric oxide synthase (iNOS) [152]. WA also inhibits vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1, which is induced by TNF-\(\alpha\) along with inducible iNOS expression and NO production induced by lipopolysaccharide-ascharide (LPS) by reducing Akt and NF-kB activation [169]. Moreover, WA inhibits microglial inflammatory response through inhibition of LPS-induced COX-2 mRNA and protein expression and production of prostaglandin E2, one of the most important products of COX-2. As a result, WA controls the microglial inflammatory response by decreasing COX-2 expression and PGE2 construction and blocking LPS-induced STAT1 and STAT3 phosphorylation [170]. There were no significant effects of WA on LPS-induced ERK and Akt phosphorylation, but WA reduced slightly the JNK-pathway and p38 phosphorylation (Figure 2). Several molecular docking studies also revealed that WA is capable of interfering with the NF-\(\kappa\)B production pathway through different mechanisms. Among these mechanisms is in silico analysis, which has shown a solid probable intermolecular interaction between WA and IKK\(\gamma\) that interrupts the development of the IKK complex and inhibits \(\kappa\)B depletion [171]. Another suggested mechanism of WA-mediated inhibition of NF-\(\kappa\)B is by straight interaction of WA with NF-\(\kappa\)B itself [172] or its Is\(\kappa\)B inhibitor [20; 172]. Thus, it was concluded that pure WA has important NF-\(\kappa\)B inhibitor activity, which makes it a novel anti-inflammatory agent for the treatment of AD [163]. Figure 2: Schematic representation showing the target sites of WA action in amyloidogenic pathway that leads to AD. WA inhibits NF-\(\kappa\)B signaling (right side). WA regulates several kinase-signaling pathways such as AKT and JAK/STAT. Abbreviations: APP: amyloid precursor protein; Aß: \(\beta\)-amyloid; TLR: Toll-like receptor; LPS: lipopolysaccharideadexidates; IKK: IxB kinase; TNF-\(\alpha\): tumor necrosis factor-\(\alpha\); IL-1ß: interleukin-1ß; MAP3K7)/TAK1: mitogen-activated protein kinase 7 (MAP3K7)/(TAK1); NF-\(\kappa\)B: nuclear factor kappa B; U: ubiquitination; JAK: Janus kinase; STAT: signal transducers and activators of transcription; PTEN: phosphatase and tension homolog; PDK1: phosphoinositide-dependent kinase-1; AD: Alzheimer disease; WA: withaferin A.  
WA Affects Inflammatoryasome Activation  
Inflammasomes, a collection of multiprotein complexes, are gathered inside the cytosol after sensing pattern-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) [173]. Once gathered, they function as a scaffold for recruitment of the inactive pro-caspase-1 zymogen that contributes to the oligomerization of the pro-caspase-1 protein and triggers their autoproteolytic cleavage into the bioactive enzyme caspase-1. The corresponding cleavage of pro-IL-18 and pro-IL-18 allows the discharge of such pro-inflammatory cytokines into the extracellular space.