Meisoindigo Protects Against Focal Cerebral Ischemia-Reperfusion Injury by Inhibiting NLRP3 Inflammasome Activation and Regulating Microglia/Macrophage Polarization via TLR4/NF-κB Signaling Pathway

Abstract

Ischemic stroke is a devastating disease with long-term disability. However, the pathogenesis is unclear and treatments are limited. Meisoindigo, a second-generation derivative of indirubin, has general water solubility and is well-tolerated. Previous studies have shown that meisoindigo reduces inflammation by inhibiting leukocyte chemotaxis and migration. In the present study, we investigated the hypothesis that meisoindigo was also protective against ischemic stroke, then evaluated its underlying mechanisms. In vivo, adult male C57BL/6J wild-type mice were used to produce a middle cerebral artery occlusion (MCAO) stroke model. On day three after reperfusion, obvious improvement in neurological scores, infarct volume reduction and cerebral edema amelioration were observed in meisoindigo treatment. Moreover, immunofluorescence staining and western-blot showed that the expression of NLRP3 inflammasome and its associated proteins in neurons and microglia was inhibited by meisoindigo. The effects of Meisoindigo on NLRP3 inflammasome inactivation and increased the M2 phenotype of microglia/macrophage through shifting from a M1 phenotype, which was possibly mediated by inhibition of TLR4/NF-κB. Furthermore, we verified the inhibitory effect of meisoindigo on TLR4/NF-κB signaling pathway, and found that meisoindigo treatment could significantly suppressed the expression of TLR4/NF-κB pathway-associated proteins in a dose-dependent manner, meanwhile, which resulted in downregulation of HMGB1 and IL-1β. Next, we established an in vitro oxygen glucose deprivation/Reperfusion (OGD/R) model in HT-22 and BV2 cells to simulate ischemic conditions. Cytotoxicity assay showed that meisoindigo substantially improved relative cell vitality and in HT-22 and BV2 cells following OGD/R in vitro. After suffering OGD/R, the TLR4/NF-κB pathway was activated, the expression of NLRP3 inflammasome-associated proteins and M1 microglia/macrophage were increased, but

Effects of β-Adrenergic Blockade on Metabolic and Inflammatory Responses in a Rat Model of Ischemic Stroke

“…Macrophages/microglia can be categorized into two phenotypes: proinflammatory and anti-inflammatory. Neuroinflammation can arise from an imbalance between proinflammatory and anti-inflammatory phenotypes favoring the former, with a reversal in the balance ameliorating disease progression, including stroke [44]. The presence of IRF5, IRF8, P2X4R, P2X7R, and P2Y12R promotes microglia polarization towards proinflammatory phenotypes, while CD163, CD206, arginase 1, Ym-1, Nrf2, Sirt1, and Heme Oxygenase-1 (HO-1) shift microglia to anti-inflammatory phenotypes [27,[45][46][47][48].…”

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway

“…Meisoindigo protected against focal cerebral ischemia-reperfusion injury by regulating microglia/macrophage polarization via NF-κB signaling pathway. 34 Candesartan was reported to reduce infarct volume and improve behavior after stroke via reducing of the TLR signaling cascade. 35 In our co-culture system, candesartan ameliorated the neurotoxic effect of M1 microglia to OGD neurons via regulating microglia polarization toward M2 phenotype.…”

miR‑183‑5p attenuates cerebral ischemia injury by negatively regulating PTEN

“…Brain injury caused by cerebral ischemia can lead to neurological deficit symptoms and local infarction ( 29 ). A previous study has demonstrated that neurological scores and cerebral edema can reflect the degree of brain damage ( 32 ). Additionally, neuronal damage and infarct size may visually indicate the extent of brain damage ( 33 ).…”