Abstract
BackgroundAndrographolide is the major labdane diterpenoid originally isolated from Andrographis paniculata and has been shown to have anti-inflammatory and antioxidative effects. However, there is a dearth of studies on the potential therapeutic utility of andrographolide in neuroinflammatory conditions. Here, we aimed to investigate the mechanisms underlying andrographolide’s effect on the expression of anti-inflammatory and antioxidant heme oxygenase-1 (HO-1) in primary astrocytes.MethodsMeasurements of the effects of andrograholide on antioxidant HO-1 and its transcription factor, Nrf2, include gene expression, protein turnover, and activation of putative signaling regulators.ResultsAndrographolide potently activated Nrf2 and also upregulated HO-1 expression in primary astrocytes. Andrographolide’s effects on Nrf2 seemed to be biphasic, with acute (within 1 h) reductions in Nrf2 ubiquitination efficiency and turnover rate, followed by upregulation of Nrf2 mRNA between 8 and 24 h. The acute regulation of Nrf2 by andrographolide seemed to be independent of Keap1 and partly mediated by p38 MAPK and ERK signaling.ConclusionsThese data provide further insights into the mechanisms underlying andrographolide’s effects on astrocyte-mediated antioxidant, and anti-inflammatory responses and support the further assessment of andrographolide as a potential therapeutic for neurological conditions in which oxidative stress and neuroinflammation are implicated.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0723-3) contains supplementary material, which is available to authorized users.
Highlights
Andrographolide is the major labdane diterpenoid originally isolated from Andrographis paniculata and has been shown to have anti-inflammatory and antioxidative effects
Andrographolide positively regulated NF-E2-related factor 2 (Nrf2) in astrocytes To assess the potential of andrographolide to induce Nrf2, a known regulator of heme oxygenase-1 (HO-1) transcription [11, 28, 29], primary astrocytes were treated with various concentrations of andrographolide for 1 h and immunoblotted with Nrf2 antibody
Independent time-course of andrographolide’s effects on Nrf2 messenger RNA (mRNA) versus protein in astrocytes we studied the time-course of both Nrf2 mRNA and protein changes in andrographolide-treated astrocytes
Summary
Andrographolide is the major labdane diterpenoid originally isolated from Andrographis paniculata and has been shown to have anti-inflammatory and antioxidative effects. We aimed to investigate the mechanisms underlying andrographolide’s effect on the expression of anti-inflammatory and antioxidant heme oxygenase-1 (HO-1) in primary astrocytes. Wong et al Journal of Neuroinflammation (2016) 13:251 from hydrogen peroxide-induced reactive oxygen species [11] Together with their well-recognized roles in facilitating neuronal trophic support, biochemical homeostasis, blood brain barrier integrity, response to neuroinflammatory signals and scar formation, astrocytes play a critical role in redox homeostasis and are the major source of antioxidant molecules and enzymes which protect them and the neurons they support from oxidative stresses [12, 13]. Because HO-1 is a known gene target of transcription factor NF-E2-related factor 2 (Nrf2), which is critically involved in cellular defense against oxidative stress [11, 28, 29], we studied andrographolide effects on astroglial Nrf regulation
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