Indirubin-3 '-oxime inhibits inflammatory activation of rat brain microglia
Graduate School of East-West Medical Science, Kyung Hee University, Yongin-si 446-701, Republic of Korea. Neuroscience Letters
(Impact Factor: 2.03).
10/2010; 487(2):139-43. DOI: 10.1016/j.neulet.2010.10.009
Microglial cells play critical roles in the immune and inflammatory responses of the brain. Under pathological conditions, the activation of microglia helps to restore brain homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory and neurotoxic factors. As such, regulators of microglial activation have been considered as potential therapeutic candidates to reduce the risk of neurodegeneration associated with neurodegenerative diseases, including Alzheimer's and, Parkinson's diseases. Indirubin-3'-oxime, a potent inhibitor of cyclin-dependent kinases and glycogen synthase kinase-3β, has been shown to have neuroprotective potential. The specific aim of this study was to examine the efficacy of indirubin-3'-oxime in the repression of microglial activation. Indirubin-3'-oxime was shown to effectively inhibit lipopolysaccharide (LPS)-induced nitric oxide release from cultured rat brain microglia. This compound reduced the LPS-stimulated productions of tumor necrosis factor-α, interleukin-1β, prostaglandin E(2), and intracellular reactive oxygen species and also effectively reduced LPS-elicited NF-κB activation. In organotypic hippocampal slice cultures, indirubin-3'-oxime blocked LPS-related hippocampal cell death. These results suggest that indirubin-3'-oxime provides neuroprotection by reducing the productions of various neurotoxic molecules in activated microglia.
Available from: ncbi.nlm.nih.gov
- "Kunikata and colleagues reported that indirubin inhibited IFN-c production from human myelomonocytic HBL-38 cells, IL-6 production by murine splenocytes, and ear swelling in a murine model of delayed-type hypersensitivity (Kunikata et al., 2000). Most recently, IO inhibited the LPS-induced production of NO, TNF-a, IL-1b, and PGE-2 by rat brain microglia cells via inhibition of NF-jB activation (Jung et al., 2011). "
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ABSTRACT: Activation of the aryl hydrocarbon receptor (AhR) in immune cells, such as dendritic cells (DCs), can lead to suppressed immune responses. Although AhR activation is most recognized for mediating the effects of its prototypical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), many compounds existing in dietary sources can also bind the AhR. Because the immunomodulatory effects of indole-3-carbinol (I3C) and indirubin-3'-oxime (IO) have yet to be investigated in DCs, we evaluated the potential immunomodulatory effects of these compounds on murine DCs. We hypothesized that I3C and IO suppress immune and inflammatory responses in DCs. We found that both I3C and IO decreased the expression of CD11c, CD40, and CD54 while they increased expression of MHC2 and CD80. Following lipopolysaccharide (LPS)-activation, I3C and IO suppressed the production of pro-inflammatory mediators including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-12, and nitric oxide but increased IL-10 levels. These effects of I3C and IO were partially mediated by the AhR. Additionally, immunoregulatory genes, such as ALDH1A, IDO and TGFB, were upregulated following treatment with I3C or IO. Both I3C and IO decreased basal levels of nuclear factor-kappa B p65, but only I3C suppressed the LPS-induced activity of RelB. Finally, when cultured with naïve T cells, bone marrow-derived dendritic cells treated with the dietary AhR ligands increased the frequency of Foxp3+ Tregs in an antigen-specific manner. Taken together, these results indicate that I3C and IO exhibit immunosuppressive and anti-inflammatory effects on DCs. Because I3C and IO are significantly less toxic than TCDD, these natural products may ultimately become useful therapeutics for the treatment of autoimmune and inflammatory diseases.
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ABSTRACT: This study is to investigate the effects of indirubin on ATP-induced immune responses of macrophages. For this, neutral red dye uptake method was used to test phagocytosis, MTT assay was used for measuring cell death, and reactive oxygen species (ROS) was tested with fluorescent probe DHE. The data showed that extracellular ATP attenuated phagocytosis, induced cell death and increased ROS production, and these effects were restored by pre-treating with indirubin. This result suggested that indirubin blockade the effects of ATP on macrophages, because extracellular ATP-induced effects are dependent on P2 receptors, in particular P2X7 receptors. Furthermore, the effects of indirubin on the activation of P2 receptors were tested, in particular P2X7 receptors. The data showed that indirubin significantly decreased ATP-induced, P2 receptors mediated intracellular Ca2+ concentration ([Ca2+]i) rise and inhibited P2X7 receptor-based ethidium bromide (EB) dye uptake. These results suggested the inhibitory effects of indirubin on the activation of P2X7 receptors, which may underlying the effects on ATP induced ROS production, phagocytosis attenuation and cell death of macrophages.
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ABSTRACT: Neuroinflammation plays a critical role in the etiology of chronic neurodegenerative diseases such as Alzheimer's disease. INM-176 is a standardized ethanolic extract of Angelica gigas, which has been traditionally used as a tonic to treat anemia. In the present study, we investigated whether INM-176 exhibits neuroprotective activities against lipopolysaccharide (LPS)-induced neuronal damage in vitro and in vivo. In primary microglial cells, INM-176 significantly inhibited LPS-induced nitric oxide release and expression of tumor necrosis factor-α and interleukin-1β. The expression levels of inducible nitric oxide synthase and cylcooxygenase-2 in BV2 microglial cells were markedly upregulated by LPS, but this increased expression was counteracted by INM-176. LPS-mediated neuronal damage in an organotypic hippocampal slice culture was also attenuated by the administration of INM-176. In addition, LPS (1 μg/2 μl, i.c.v.)-induced cognitive dysfunction in mice, as determined by passive avoidance and Y-maze tasks, was significantly attenuated by the administration of INM-176. Furthermore, the activation of microglia or astrocytes by LPS in the hippocampal regions of mice was suppressed by INM-176. These results suggest that the neuroprotective and cognition ameliorating effects of INM-176 against LPS-induced damage are mediated, in part, by its anti-inflammatory activities.
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