Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia

PLoS One. 2015 Feb 19;10(2):e0118372. doi: 10.1371/journal.pone.0118372. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Blotting, Western
  • Cell Line
  • Cell Survival / drug effects
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Cytokines / metabolism
  • Cytoskeleton / drug effects
  • HSP70 Heat-Shock Proteins / metabolism
  • Lipopolysaccharides / toxicity
  • Mice
  • Microglia / cytology
  • Microglia / drug effects
  • Microglia / metabolism
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Thiamine / analogs & derivatives*
  • Thiamine / pharmacology

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • HSP70 Heat-Shock Proteins
  • Lipopolysaccharides
  • Protein Kinase Inhibitors
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Thiamine
  • benphothiamine

Grant support

This work was supported by Ministry of Education, Science and Technological Development of the Republic of Serbia Grant III 41014. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.