Benfotiamine Attenuates Inflammatory Response in LPS Stimulated BV-2 Microglia

Abstract

Microglial cells are resident immune cells of the central nervous system (CNS), recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine) derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro-inflammatory mediators such as inducible form of nitric oxide synthase (iNOS) and NO; cyclooxygenase-2 (COX-2), heat-shock protein 70 (Hsp70), tumor necrosis factor alpha α (TNF-α), interleukin-6 (IL-6), whereas it increased anti-inflammatory interleukin-10 (IL-10) production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the nucleus. Therefore, benfotiamine may have therapeutic potential for neurodegenerative diseases by inhibiting inflammatory mediators and enhancing anti-inflammatory factor production in activated microglia.

SMEAF attenuates the production of pro-inflammatory mediators through the inactivation of Akt-dependent NF-κB, p38 and ERK1/2 pathways in LPS-stimulated BV-2 microglial cells

“…Interestingly, this study showed that SMEAF markedly suppressed the COX-2 protein expression in BV-2 cells, implying the involvement of PGE2 in SMEAF anti-inflammatory action that is associated with downregulation of COX-2 protein expression level in LPS-stimulated BV-2 cells. Additionally, a previous study has shown that high levels of NO could induce COX-2 expression, suggesting that a compound capable of down-modulating COX-2 expression may potentially exert an anti-inflammatory effect (Bozic et al, 2015;Minghetti, 2004). Thus, the present findings suggest that SMEAF may have protective effects on neurodegenerative diseases induced by neuroinflammation.…”

Delayed activation of human microglial cells by high dose ionizing radiation

“…IL-10 is an anti-inflammatory and immunoregulatory cytokine. Several studies have demonstrated that IL-10 inhibited the production of pro-inflammatory cytokines by reactive glia in response to LPS (Bozic et al, 2015;Cianciulli et al, 2015;Molina-Holgado et al, 2001;Szczepanik et al, 2001).…”

Balancing the immune response in the brain: IL-10 and its regulation

“…Prostaglandin E 2 , an immune mediator present in inflammatory settings, is another example of molecules that enhance LPS-induced IL-10 expression and secretion [88]. Benfotiamine, a synthetic vitamin B1 derivate, downregulates the production of pro-inflammatory cytokines by TLR4-stimulated BV2 microglia cell line, whereas up-regulating that of IL-10 [89]. Mycoepoxydiene was also shown to potentiate IL-10 production by TLR4-activated microglial cells, therefore reducing inflammatory markers [90].…”