Genistein-3'-sodium sulfonate Attenuates Neuroinflammation in Stroke Rats by Down-Regulating Microglial M1 Polarization through α7nAChR-NF-κB Signaling Pathway

Int J Biol Sci. 2021 Mar 8;17(4):1088-1100. doi: 10.7150/ijbs.56800. eCollection 2021.

Abstract

Microglial M1 depolarization mediated prolonged inflammation contributing to brain injury in ischemic stroke. Our previous study revealed that Genistein-3'-sodium sulfonate (GSS) exerted neuroprotective effects in ischemic stroke. This study aimed to explore whether GSS protected against brain injury in ischemic stroke by regulating microglial M1 depolarization and its underlying mechanisms. We established transient middle cerebral artery occlusion and reperfusion (tMCAO) model in rats and used lipopolysaccharide (LPS)-stimulated BV2 microglial cells as in vitro model. Our results showed that GSS treatment significantly reduced the brain infarcted volume and improved the neurological function in tMCAO rats. Meanwhile, GSS treatment also dramatically reduced microglia M1 depolarization and IL-1β level, reversed α7nAChR expression, and inhibited the activation of NF-κB signaling in the ischemic penumbra brain regions. These effects of GSS were further verified in LPS-induced M1 depolarization of BV2 cells. Furthermore, pretreatment of α7nAChR inhibitor (α-BTX) significantly restrained the neuroprotective effect of GSS treatment in tMCAO rats. α-BTX also blunted the regulating effects of GSS on neuroinflammation, M1 depolarization and NF-κB signaling activation. This study demonstrates that GSS protects against brain injury in ischemic stroke by reducing microglia M1 depolarization to suppress neuroinflammation in peri-infarcted brain regions through upregulating α7nAChR and thereby inhibition of NF-κB signaling. Our findings uncover a potential molecular mechanism for GSS treatment in ischemic stroke.

Keywords: Genistein-3′-sodium sulfonate.; Ischemic stroke; Microglia polarization; Neuroinflammation; α7nAChR-NF-κB signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Infarction / prevention & control*
  • Cell Line
  • Drug Evaluation, Preclinical
  • Genistein / analogs & derivatives*
  • Genistein / pharmacology
  • Genistein / therapeutic use
  • Ischemic Stroke / drug therapy*
  • Ischemic Stroke / metabolism
  • Male
  • Mice
  • Microglia / drug effects*
  • NF-kappa B / metabolism*
  • Neuroinflammatory Diseases / prevention & control
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*

Substances

  • NF-kappa B
  • alpha7 Nicotinic Acetylcholine Receptor
  • genistein-3'-sodium sulfonate
  • Genistein