Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia

• Published in: PloS one Vol. 10; no. 2; p. e0118372
• Main Authors: Bozic, Iva, Savic, Danijela, Laketa, Danijela, Bjelobaba, Ivana, Milenkovic, Ivan, Pekovic, Sanja, Nedeljkovic, Nadezda, Lavrnja, Irena
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19-02-2015; Public Library of Science (PLoS)
• Subjects: Activation; Adenosine; AKT protein; Animals; Anti-Inflammatory Agents - pharmacology; B cells; Beta cells; Biochemistry; Blotting, Western; Brain research; c-Jun protein; Cell Line; Cell Survival - drug effects; Central nervous system; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytokines; Cytokines - metabolism; Cytoskeleton - drug effects; Diabetes; Diabetes mellitus; Diabetic neuropathy; Disease; Extracellular signal-regulated kinase; Health aspects; Heat shock proteins; Homeostasis; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Immune system; Inflammatory response; Interleukin; Interleukin 10; Interleukin 6; JNK protein; Kinases; Laboratories; Lipopolysaccharides; Lipopolysaccharides - toxicity; Medical treatment; Metabolism; Mice; Microglia; Microglia - cytology; Microglia - drug effects; Microglia - metabolism; Microglial cells; Microscopy, Fluorescence; Mitogen-Activated Protein Kinases - metabolism; Morphology; Nervous system; Nervous system diseases; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neuropathy; Neurosciences; NF-κB protein; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Nuclei (cytology); Oxidative stress; Phosphorylation; Physiology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Rodents; Signal Transduction - drug effects; Thiamine; Thiamine - analogs & derivatives; Thiamine - pharmacology; Transcription factors; Translocation; Vitamin B; Vitamin B1; Vitamin deficiency; Austria; Serbia; United States > US; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0118372

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.