Abstract
The activation of microglia is decisively involved with the neurodegeneration observed in many neuroinflammatory pathologies, such as multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. Tectorigenin (TEC) is an isoflavone isolated from various medicinal plants, such as Pueraria thunbergiana Benth, Belamcanda chinensis, and Iris unguicularis. In the present study, the neuroinflammatory effects of TEC were evaluated in both lipopolysaccharide (LPS)-treated BV-2 microglial and mouse models. TEC remarkably inhibited reactive oxygen species (ROS) generation. TEC also inhibits the production and expression of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in LPS-stimulated BV-2 cells. In addition, TEC suppressed the LPS-induced activation of nuclear factor-κB (NF-κB), phosphorylation of extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) to regulate the inflammatory mediators, such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6. These results indicate that TEC may inhibit neuronal inflammation through the downregulation of inflammatory mediators, including iNOS, COX-2, TNF-α, and IL-6 by suppressing NF-κB/ERK/JNK-related signaling pathways. Furthermore, cotreatment with TEC and ERK inhibitor SCH772984 or JNK inhibitor SP600125 suppressed the overproduction of LPS-induced NO production in BV-2 cells. Consistent with the results of in vitro experiments, an LPS-induced brain inflammation mouse model, administration of TEC effectively decrease the levels of malondialdehyde, iNOS in hippocampus, and prevented increases in the levels of TNF-α and IL-6 in the serum. TEC showed marked attenuation of microglial activation. Finally, TEC inhibited protein expression of toll-like receptor 4 and myeloid differentiation factor 88 in LPS-activated BV-2 microglia and mouse models. Taken altogether, the cumulative findings suggested that TEC holds the potential to develop as a neuroprotective drug for the intervention of neuroinflammatory disorders.
Highlights
Neuroinflammation is characterized by microglial activation and has been closely associated with the pathogenesis of Alzheimer’s disease (AD), as well as several other neurodegenerative disorders, including Parkinson’s disease (Liu and Hong, 2003)
To ascertain the non-toxic concentration of the combination of TEC and LPS in BV-2 cells, cells were pretreated with TEC (25, 50, or 100 μM) for 2 h followed by treatment with LPS (1 μg/mL) for 22 h
Cell viability approached ≥ 90% under all experimental conditions, indicating no cytotoxicity of TEC in LPS-treated BV-2 cells (Figure 1C). These results suggest that TEC did not affect the viability of LPS-stimulated microglial cells
Summary
Neuroinflammation is characterized by microglial activation and has been closely associated with the pathogenesis of Alzheimer’s disease (AD), as well as several other neurodegenerative disorders, including Parkinson’s disease (Liu and Hong, 2003). Oxidative stress, which is characterized by the aberrant production of reactive oxygen species (ROS) and failure of the antioxidant defense system, has been associated with neurodegenerative diseases such as AD (Uttara et al, 2009; Gonzalez-Reyes et al, 2013). Cognitive deficits associated with AD are the result of increased susceptibility to oxidative stress and neuroinflammation (Uttara et al, 2009). Inhibiting the aberrant activation of microglia may have therapeutic potential in the treatment of neuroinflammation-related neurodegenerative diseases
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