Andrographolide Inhibits PI3K/AKT-Dependent NOX2 and iNOS Expression Protecting Mice against Hypoxia/Ischemia-Induced Oxidative Brain Injury

Abstract

This study aimed to explore the mechanisms by which andrographolide protects against hypoxia-induced oxidative/nitrosative brain injury provoked by cerebral ischemic/reperfusion (CI/R) injury in mice. Hypoxia IN VITRO was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone CI/R injury with andrographolide (10-100 µg/kg, i. v.) at 1 h after hypoxia ameliorated CI/R-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. CI/R induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (NOX2), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b cells due to activation of nuclear factor-kappa B (NF- κB) and hypoxia-inducible factor 1-alpha (HIF-1 α). All these changes were significantly diminished by andrographolide. In BV-2 cells, OGD induced ROS and nitric oxide production by upregulating NOX2 and iNOS via the phosphatidylinositol-3-kinase (PI3K)/AKT-dependent NF- κB and HIF-1 α pathways, and these changes were suppressed by andrographolide and LY294002. Our results indicate that andrographolide reduces NOX2 and iNOS expression possibly by impairing PI3K/AKT-dependent NF- κB and HIF-1 α activation. This compromises microglial activation, which then, in turn, mediates andrographolide's protective effect in the CI/R mice.

Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1α signaling

“…Consistent with the previous study, we found that hypoxia enhanced RAFLS migration and invasion, indicating the involvement of hypoxia in the pathogenesis of RA. Andrographolide has been suggested to protect against hypoxiainduced oxidative/nitrosative injury in mice [19]. In the present study, we found that andrographolide inhibited hypoxia-induced migration and invasion of RA-FLSs in a dose-dependent manner.…”

“…Previous studies revealed that andrographolide protects hypoxiainduced oxidative/nitrosative brain injury in mice [19] and downregulates HIF-1α in human non-small cell lung cancer A549 cells [20]. Considering the important role of hypoxia in the pathogenesis of RA, it would be interesting to investigate the effects of andrographolide on hypoxia-induced pathological changes.…”

A novel bioactivity of andrographolide fromAndrographis paniculataon cerebral ischemia/reperfusion-induced brain injury through induction of cerebral endothelial cell apoptosis

“…It suggests that the deteriorating effect of andrographolide on brain injury, in part, is associated with its capacity to induce CEC apoptosis. On the other hand, previous studies showed that andrographolide at a rather low dose (0.1 mg/kg) could protect neuronal function against inflammation from ischemia/reperfusion-induced brain injury in a rat or mouse model (Chan et al, 2010;Chern et al, 2011). This evidence indicate that andrographolide at a rather low dose (0.1 mg/kg) protects against brain injury, but it worsens brain injury at a higher dose (5 mg/kg).…”

Andrographolide a New Potential Drug for the Long Term Treatment of Rheumatoid Arthritis Disease

“…The use of an ERK inhibitor in the animal model of collagen-induced arthritis suppressed the antigen-specific activation of T cells [78]. In vitro, andrographolide reduced the Akt phosphorylation in macrophages, HUVEC and microglia, and decreased the ERK1/2 phosphorylation in macrophages, suggesting that the signaling pathways PI3K/Akt and ERk1/2 may be associated to its anti-inflammatory effect [24,61,79]. Additionally, andrographolide also have the ability to reduce ERK1 and ERK5 phosphorylation [57].…”