Wogonin attenuates endotoxin‐induced prostaglandin E2 and nitric oxide production via Src‐ERK1/2‐NFκB pathway in BV‐2 microglial cells

Abstract

Microglia are the major component of intrinsic brain immune system in neuroinflammation. Although wogonin expresses anti-inflammatory function in microglia, little is known about the molecular mechanisms of the protective effect of wogonin against microglia activation. The aim of this study was to evaluate how wogonin exerts its anti-inflammatory function in BV2 microglial cells after LPS/INFγ administration. Wogonin not only inhibited LPS/ INFγ-induced PGE2 and NO production without affecting cell viability but also exhibited parallel inhibition on LPS/INFγ-induced expression of iNOS and COX-2 in the same concentration range. While LPS/INFγ-induced expression of P-p65 and P-IκB was inhibited by wogonin-only weak inhibition on P-p38 and P-JNK were observed, whereas it significantly attenuated the P-ERK1/2 and its upstream activators P-MEK1/2 and P-Src in a parallel concentration-dependent manner. These results indicated that the blockade of PGE2 and NO production by wogonin in LPS/INFγ-stimulated BV2 cells is attributed mainly to interference in the Src-MEK1/2-ERK1/2-NFκB-signaling pathway.

Anti-inflammatory effects of thymoquinone in activated BV-2 microglial cells

“…In general pro-inflammatory processes associated with activated BV-2 microglial cells involved a number of signaling pathways that involve Src-MEK1/2-ERK1/2 (Manivannan et al, 2013, Yeh et al, 2013) p38MAPK phosphorylation (Kim et al, 2013a), phosphorylation of c-Jun N-terminal kinase and the nuclear translocation of NF-kappaB p65 (Jung et al, 2013, More et al, 2013) /activation of NFkappaB-signaling pathway (Yeh, Yang, 2013) or down-regulation of HO-1 / and PKA-mediated CREB phosphorylation. (Park et al, 2012) Future studies will be required to further corroborate these signaling pathways to be involved with the anti-inflammatory effects of TQ.…”

Neuroinflammatory processes in cognitive disorders: Is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects?

“…For example, treatment with apigenin (25 µM) or luteolin (25 µM) alleviated microglia-induced neuroinflammatory response (TNF-α, IL-6) by suppressing CD40 receptor expression in a STAT1-dependent manner (Rezai-Zadeh et al, 2008). Similarly, wogonin (3-10 µM) was shown to alleviate the inflammatory response in activated microglial cells by reducing ERK phosphorylation, while not affecting JNK/p38 activies, although at a higher concentration (30 µM) the expression of the three MAPKs were decreased (Yeh et al, 2014). In high fat fed C57Bl/6 mice supplemented with luteolin (10mg/kg) for 16 weeks, spatial memory was improved along with a decreased expression of inflammatory markers TNF-α, IL-1β, IL-6 and NF-kB, oxidative stress and neuronal insulin resistance, and an increased production of BDNF and synaptic proteins .…”

“…To date, evidence related to the anti-neuroinflammatory effect of flavonoids predominantly derives from in vitro and animal studies and currently supports: 1) a capacity to downregulate the activity of proinflammatory transcription factors such as NF-κB, nuclear factor erythroid 2-related factor 2 (Nrf2) or STAT through their influences on a number of glial and neuronal signalling pathways, 2) an inhibitory role on the release of cytokines, such as IL-1β and TNF-α, from activated microglia, 3) an inhibitory action against the production of NO and PGE2 in response to microglia activation, 4) an ability to inhibit the activation of NADPH oxidase and subsequent ROS generation in activated glial cells, and 5) an inhibitory action against activated microglia through TLR receptors or insulin resistance (Gonzalez-Gallego et al, 2010;Vauzour, 2014). (Suk et al, 2003;Yeh et al, 2014). In addition, orientin (10-40 µM; extracted from Trollius chinensis), tangeretin (80 µM; a flavonoid from citrus fruit peels) and quercetin (20-30 µM) all reduced LPS-induced NF-κB expression in BV-2 microglial cells (Kang et al, 2013;Shu et al, 2014;Zhou et al, 2014).…”

“…In addition to the inhibition of iNOS and subsequent NO production, apigenin (10 µM) (Ha et al, 2008) and wogonin (10-30 µM) (Yeh et al, 2014), also decrease the COX-2-dependent PGE2 production in LPS-activated BV-2 cells. One possible explanation for the impact of flavonoids on NO and PGE2 production could stem from the inhibition of upstream signalling molecules such as MAPKs, as observed by the decrease of JNK and p38 phosphorylation in presence of apigenin (10 µM) on LPS-induced microglial cells (Ha et al, 2008).…”

High‐dose wogonin exacerbates DSS‐induced colitis by up‐regulating effector T cell function and inhibiting Treg cell

“…The flavonoid (30 μM) could attenuate endotoxin‐induced prostaglandin E2 and nitric oxide production via the Src‐Erk1/2‐NF‐κB pathway in BV‐2 microglial cells 18. Wogonin (40 mg/kg) reduced the activation of TLR4/NF‐κB signalling after experimental traumatic brain injury 19.…”