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.
Highlights
Microglia are resident immune cells in the central nervous system (CNS), involved in its immune surveillance and continuous scanning for signs of danger [1,2]
Crystal violet and trypan blue exclusion viability assay revealed that cell viability of BV-2 cells exposed with or without LPS was not affected in the presence of benfotiamine, in neither one of the concentrations tested (Fig. 1D; S1D and S2 Figs.)
To confirm the involvement of the extracellular signal-regulated kinases 1/2 (ERK1/2), Jun N-terminal kinases (JNK) and Akt signaling pathways in the antiinflammatory effects of benfotiamine, we examined the effect of their pharmacological inhibitors on microglial activation
Summary
Microglia are resident immune cells in the central nervous system (CNS), involved in its immune surveillance and continuous scanning for signs of danger [1,2]. Microglia undergoes dramatic morphologic changes, from resting ramified shape into activated amoeboid morphology [5,6,7] These changes are concomitant with up-regulation of several transcription factors (e.g. NF-κB) and release of soluble factors, such as proinflammatory cytokines, chemokines [8] and reactive oxygen species [9]. Together, these processes play a critical role in the neuronal damage in various neurodegenerative diseases [10]. It is important to investigate the negative regulators of microglial activation and their underlying molecular mechanisms
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