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

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.

Insight into the Neuroprotective Effect of Genistein-3′-sodium sulfonate against Neonatal Hypoxic-Ischaemic Brain Injury in Rats by Bioinformatics

“…Furthermore, GSS can upregulate α7nAChR expression to inhibit the NF-κB pathway, decrease the number of M1 microglia, and inhibit neuroin ammation in tMCAO rats [14,15]. In this study, we found that GSS signi cantly reduces the cerebral infarct volume of HIE neonatal rats, which we suspect is a promising pharmacological agent to treat HIE, but its molecular target is still unknown.…”

Icaritin inhibits neuroinflammation by regulating microglial polarization through GPER-ERK-NF-κB signaling pathway in cerebral ischemic rat

“…When NF-κB is activated, it is phosphorylated and translocates to the nucleus, where it mediates in ammatory brain injury by inducing the transcription of many proin ammatory genes, such as IL-1β and TNF-α (Zhang et al, 2019). In vivo, genistein-3′-sodium sulfonate, a structural modi er of the phytoestrogen genistein, was shown to inhibit the activation and nuclear translocation of NF-κB and reduce the M1 polarization of microglia, thereby inhibiting neuroin ammation in tMCAO rats (Liu et al, 2021). Multiple in vitro studies have also demonstrated that NF-κB is involved in microglial activation and M1 polarization (Kong et al, 2022;Liu et al, 2019b).…”

“…The rat tMCAO model was constructed by the modi ed Zea Longa suture method as described previously (Li et al, 2017;Liu et al, 2021;Shan et al, 2021). Rats were anesthetized by intraperitoneal injection of 1% pentobarbital sodium at a dose of 4.5 mL/kg.…”

“…The brain slices were stained with 0.5% TTC in a 37°C water bath for 15 min in the dark, washed with PBS, and then xed with 4% paraformaldehyde (PFA) for 4-6 h. The slices were scanned with a scanner, and the brain infarct area was analyzed with ImageJ software (National Institutes of Health, Bethesda, MD, USA). The percentage of cerebral infarct volume (%) was calculated as (contralateral hemisphere volume -noninfarct ipsilateral hemisphere volume)/2 × contralateral hemisphere volume × 100 (Liu et al, 2021).…”

The Role of Concomitant Nrf2 Targeting and Stem Cell Therapy in Cerebrovascular Disease

“…In models of ischemia, STVNA has been implicated in inhibition of astrogliosis [ 210 ], modulation of microglia/macrophage polarization [ 211 ], and preservation of volume control in endothelial cells [ 212 ]. Flavonoids constitute a class of natural products with a significant role in the inhibition of microglial polarization and management of oxidative stress, with a number of compounds acting upon the NF-κB signaling pathway [ 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 ]. A number of the flavonoids have been implicated in the activity of stem cells, including hesperetin in NSC proliferation [ 221 ], icariin in neurogenesis and angiogenesis through release of BDNF and VEGF [ 222 ], and quercetin in enhancing stem cell viability and proliferation while reducing apoptosis [ 223 ].…”