Abstract
Chronic microglial activation and resulting sustained neuroinflammatory reaction are generally associated with neurodegeneration. Activated microglia acquires proinflammatory cellular profile that generates oxidative burst. Their persistent activation exacerbates inflammation, which damages healthy neurons via cytotoxic mediators, such as superoxide radical anion and nitric oxide. In our recent study, we have shown that benfotiamine (S-benzoylthiamine O-monophosphate) possesses anti-inflammatory effects. Here, the effects of benfotiamine on the pro-oxidative component of activity of LPS-stimulated BV-2 cells were investigated. The activation of microglia was accompanied by upregulation of intracellular antioxidative defense, which was further promoted in the presence of benfotiamine. Namely, activated microglia exposed to non-cytotoxic doses of benfotiamine showed increased levels and activities of hydrogen peroxide- and superoxide-removing enzymes—catalase and glutathione system, and superoxide dismutase. In addition, benfotiamine showed the capacity to directly scavenge superoxide radical anion. As a consequence, benfotiamine suppressed the activation of microglia and provoked a decrease in NO and ·O−2 production and lipid peroxidation. In conclusion, benfotiamine might silence pro-oxidative activity of microglia to alleviate/prevent oxidative damage of neighboring CNS cells.
Highlights
Neurons are very susceptible to oxidative stress, as a result of great metabolic rate, large oxygen consumption, relatively weak antioxidative defense, low regenerative capacity, and specific cellular geometry (Andersen, 2004; Barnham et al, 2004)
Benfotiamine Suppresses LPS-induced CD40 Expression in BV-2 Cells CD40 expression by BV-2 cells was used as an indicator of microglial activation (Qin et al, 2005)
In control BV-2 cells constitutive expression of surface CD40 was low, and only about 100 per 10,000 cells analyzed by FACS expressed CD40 receptor (Figure 1)
Summary
Neurons are very susceptible to oxidative stress, as a result of great metabolic rate, large oxygen consumption, relatively weak antioxidative defense, low regenerative capacity, and specific cellular geometry (Andersen, 2004; Barnham et al, 2004). Current knowledge of neurological disorders, from ischemia and brain injury to psychiatric disorders and neurodegenerative diseases, indicates that pathological mechanisms involve acute or chronic activation of microglia and resulting overproduction of reactive oxygen (ROS) and nitrogen species (RNS) by the cells (Uttara et al, 2009; Rojo et al, 2014). These immune cells of the brain are on the constant patrol for invading pathogens and metabolic, ischemic or traumatic brain damage (Aguzzi et al, 2013; Gertig and Hanisch, 2014). A novel drug for treatment of multiple sclerosis— dimethyl fumarate, affects ROS and RNS production by microglia via upregulation of intracellular antioxidative system (Wilms et al, 2010; Lin et al, 2011)
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